silica dust, crystalline, in the form of quartz or cristobalite

SILICA DUST, CRYSTALLINE, IN THE FORM OF QUARTZ OR CRISTOBALITE

Silica was considered by previous IARC Working Groups in 1986, 1987, and 1996 (IARC, 1987a, b, 1997). Since that time, new data have become available, these have been incorporated in the Monograph, and taken into consideration in the present evaluation.

1. Exposure Data

Silica, or silicon dioxide (SiO2), is a group IV metal oxide, which naturally occurs in both crystalline and amorphous forms (i.e. polymor-phic; NTP, 2005). The various forms of crystal-line silica are: α-quartz, β-quartz, α-tridymite, β-tridymite, α-cristobalite, β-cristobalite, keatite, coesite, stishovite, and moganite (NIOSH, 2002). The most abundant form of silica is α-quartz, and the term quartz is often used in place of the general term crystalline silica (NIOSH, 2002).

1.1 Identification of the agent

α-Quartz is the thermodynamically stable form of crystalline silica in ambient conditions. The overwhelming majority of natural crystal-line silica exists as α-quartz. The other forms exist in a metastable state. The nomenclature used is that of α for a lower-temperature phase, and β for a higher-temperature phase. Other notations exist and the prefixes low- and high- are also used (IARC, 1997). The classification and nomenclature of silica forms are summarized in Table 1.1. For more detailed information, refer to the previous IARC Monograph (IARC, 1997).

1.2 Chemical and physical properties of the agent

Selected chemical and physical properties of silica and certain crystalline polymorphs are summarized in Table 1.1. For a detailed discus-sion of the crystalline structure and morphology of silica particulates, and corresponding phys-ical properties and domains of thermodynamic stability, refer to the previous IARC Monograph (IARC, 1997).

1.3 Use of the agent

The physical and chemical properties of silica make it suitable for many uses. Most silica in commercial use is obtained from naturally occurring sources, and is categorized by end-use or industry (IARC, 1997; NTP, 2005). The three predominant commercial silica product catego-ries are: sand and gravel, quartz crystals, and diatomites.

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1.3.1 Sand and gravel

Although silica sand has been used for many different purposes throughout history, its most ancient and principal use has been in the manufacture of glass (e.g. containers, flat plate and window, and fibreglass). Sands are used in ceramics (e.g. pottery, brick, and tile), foundry (e.g. moulding and core, refractory), abrasive (e.g. blasting, scouring cleansers, sawing and sanding), hydraulic fracturing applications, and many other uses. Several uses require the material to be ground (e.g. scouring cleansers, some types of fibreglass, certain foundry applications). In some uses (e.g. sandblasting, abrasives), grinding

also occurs during use. For a more complete list of end-uses, refer to Table 8 of the previous IARC Monograph (IARC, 1997).

According to the US Geological Survey, world production in 2008 was estimated to be 121 million metric tons (Dolley, 2009). The leading producers were the USA (30.4 million metric tons), Italy (13.8 million metric tons), Germany (8.2 million metric tons), the United Kingdom (5.6 million metric tons), Australia (5.3 million metric tons), France (5 million metric tons), Spain (5 million metric tons), and Japan (4.5 million metric tons).

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Table 1.1 Nomenclature, CAS numbers, and classification of silica forms with selected physical and chemical properties

Name CAS No. Basic Formula

Classification Synonyms Properties

Silica 7631-86-9 SiO2 α-quartz, β-quartz; α-tridymite, β1-tridymite, β2-tridymite; α-cristobalite, β-cristobalite; coesite; stishovite; moganite

Structure: crystalline, amorphous, cryptocrystallineMolecular weight: 60.1Solubility: poorly soluble in water at 20 °C and most acids; increases with temperature and pHReactivity: reacts with alkaline aqueous solutions, with hydrofluoric acid (to produce silicon tetrafluoride gas), and catechol

Crystalline SilicaCristobalite 14464-46-1 α-cristobalite,

β-cristobaliteQuartz 14808-60-7 α-quartz, β-quartz α-quartz: agate;

chalcedony; chert; flint; jasper; novaculite; quartzite; sandstone; silica sand; tripoli

Solubility: 6–11 μg/cm3 (6–11 ppm) at room temperature; slightly soluble in body fluidsThermodynamic properties: melts to a glass; coefficient of expansion by heat—lowest of any known substance

Tripoli 1317-95-9Tridymite 15468-32-3 α-tridymite,

β1-tridymite, β2-tridymite

From IARC (1997), NIOSH (2002), NTP (2005)

Silica dust, crystalline (quartz or crystobalite)

1.3.2 Quartz crystals

Quartz has been used for several thousand years in jewellery as a gem stone (e.g. amethyst, citrine), and is used extensively in both the electronics and optical components industries. Electronic-grade quartz is used in electronic circuits, and optical-grade quartz is used in windows, and other specialized devices (e.g. lasers) (IARC, 1997).

1.3.3 Diatomites

Diatomites are used in filtration, as fillers (in paint, paper, synthetic rubber goods, labo-ratory absorbents, anti-caking agents, and scouring powders), and as carriers for pesticides. They impart abrasiveness to polishes, flow and colour qualities to paints, and reinforcement to paper. Other uses include: insulators, absorption agents, scourer in polishes and cleaners, catalyst supports, and packing material (IARC, 1997).

According to the US Geological Survey, world production in 2008 was estimated to be 2.2 million metric tons. The USA accounted for 35% of total world production, followed by the People’s Republic of China (20%), Denmark (11%), Japan (5%), Mexico (4%), and France (3%) (Crangle, 2009).

1.4 Environmental occurrence

Keatite, coesite, stishovite, and moganite are rarely found in nature. The most commonly occurring polymorphs are quartz, cristobalite and tridymite, which are found in rocks and soil. These forms of silica can be released to the environment via both natural and anthropo-genic sources (e.g. foundry processes, brick and ceramics manufacturing, silicon carbide produc-tion, burning of agricultural waste or products, or calcining of diatomaceous earth). Some of these anthropogenic activities may cause transforma-tion of one polymorph into another (NIOSH, 2002).

1.4.1 Natural occurrence

α-Quartz is found in trace to major amounts in most rock types (e.g. igneous, sedimentary, metamorphic, argillaceous), sands, and soils. The average quartz composition of major igneous and sedimentary rocks is summarized in Table 10 of the previous IARC Monograph (IARC, 1997). Quartz is a major component of soils, composing 90–95% of all sand and silt fractions in a soil. It is the primary matrix mineral in the metalliferous veins of ore deposits, and can also be found in semiprecious stones, such as amethyst, citrine, smoky quartz, morion, and tiger’s eye (IARC, 1997).

Crystalline tridymite and cristobalite are found in acid volcanic rocks. Cristobalite also occurs in some bentonite clays, and as traces in diatomite. Although rarely found in nature, coesite and stishovite have been found in rocks that equilibrated in short-lived high-pressure environments (e.g. meteoritic impact craters), and keatite has been found in high-altitude atmospheric dusts, which are believed to origi-nate from volcanic sources (IARC, 1997).

For a more detailed description of the natural occurrence of crystalline silica and its poly-morphs in air, water and soil, refer to the previous IARC Monograph (IARC, 1997).

1.5 Human exposure

1.5.1 Exposure of the general population

Inhalation of crystalline silica during the use of commercial products containing quartz is thought to be the primary route of exposure for the non-occupationally exposed (i.e. general) population. Commercial products containing quartz include: cleansers, cosmetics, art clays and glazes, pet litter, talcum powder, caulk, putty, paint, and mortar. No quantitative data on potential levels of exposurem during the use of these products were available at the time of

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writing (WHO, 2000). The general population may also be exposed via ingestion of potable water containing quartz particles; however, quantitative data on concentrations of quartz in potable or other forms of drinking-water were again not available (IARC, 1997; WHO, 2000).

1.5.2 Occupational exposure

Because of the extensive natural occurrence of crystalline silica in the earth’s crust and the wide uses of the materials in which it is a constit-uent, workers may be exposed to crystalline silica in a large variety of industries and occupations (IARC, 1997). Table 1.2 lists the main industries and activities in which workers could be exposed to crystalline silica. Included in this table are activities that involve the movement of earth (e.g. mining, farming, construction, quarrying), disturbance of silica-containing products (e.g. demolition of masonry and concrete), handling or use of sand- and other silica-containing prod-ucts (e.g. foundry processes, such as casting, furnace installation and repair; abrasive blasting; production of glass, ceramics, abrasives, cement, etc.).

Estimates of the number of workers poten-tially exposed to respirable crystalline silica have been developed by the National Institute of Occupational Safety and Health (NIOSH) in the USA and by CAREX (CARcinogen EXposure) in Europe. Based on the National Occupational Exposure Survey (NOES), conducted during 1981–83, and the County Business Patterns 1986, NIOSH estimated that about 1.7 million US workers were potentially exposed to respir-able crystalline silica (NIOSH, 2002). Based on occupational exposure to known and suspected carcinogens collected during 1990–93, the CAREX database estimates that more than 3.2 million workers in the then 15 Member States of the European Union during 1990–93 were considered as occupationally exposed to respirable crystalline silica above background

level (Kauppinen et al., 2000). Nearly 87% of these workers were employed in ‘construction’ (n = 2080000), ‘manufacture of other non-metallic mineral products’ (n = 191000), ‘other mining’ (n = 132000), ‘manufacture of pottery, china and earthenware’ (n = 96000), ‘manufac-ture of machinery except electrical’ (n = 78000), ‘iron and steel basic industries’ (n = 68000), ‘manufacture of fabricated metal products, except machinery and equipment’ (n = 68000), and ‘metal ore mining’ (n = 55000). The coun-tries with the highest number of potentially exposed workers were: Germany (1 million workers), the United Kingdom (580000 workers), Spain (400000 workers), Italy (250000 workers), the Netherlands (170000 workers), France (110000 workers), and Austria (100000 workers) (Kauppinen et al., 2000; Mirabelli & Kauppinen, 2005; Scarselli et al., 2008).

For representative data in the main industries where quantitative exposure levels were available in the published literature and/or where major occupational health studies had been conducted, refer to the previous IARC Monograph (IARC, 1997). These main industries include mines and quarries, foundries and other metallurgical operations, ceramics and related industries, construction, granite, crushed stone and related industries, sandblasting of metal surfaces, agri-culture, and miscellaneous other operations (IARC, 1997). Data from studies and reviews on crystalline silica exposure published since the previous IARC Monograph are summarized below.

(a) Levels of occupational exposure

To estimate the number of US workers poten-tially exposed to high levels of crystalline silica and to examine trends in exposure over time, Yassin et al. (2005) analysed data contained in the OSHA Integrated Management Information System (IMIS) database. After exclusion of duplicate bulk and area samples, a total of 7209 personal sample measurements collected during

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2512 OSHA inspections during 1988–2003 were analysed. The findings suggest that geometric mean crystalline silica exposure levels declined in some high-risk construction industries during the period under study, and revealed a significant

decline when compared with silica exposure levels found in a previous study by Stewart & Rice (1990). Geometric mean airborne silica exposure levels among workers in the following industries were significantly lower in 1988–2003

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Table 1.2 Main activities in which workers may be exposed to crystalline silica

Industry/activity Specific operation/task Source material

Agriculture Ploughing, harvesting, use of machinery SoilMining and related milling operations

Most occupations (underground, surface, mill) and mines (metal and non-metal, coal)

Ores and associated rock

Quarrying and related milling operations

Crushing stone, sand and gravel processing, monumental stone cutting and abrasive blasting, slate work, diatomite calcination

Sandstone, granite, flint, sand, gravel, slate, diatomaceous earth

Construction Abrasive blasting of structures, buildings Highway and tunnel construction Excavation and earth-moving Masonry, concrete work, demolition

Sand, concrete Rock Soil and rock Concrete, mortar, plaster

Glass, including fibreglass Raw material processing Refractory installation and repair

Sand, crushed quartz Refractory materials

Cement Raw materials processing Clay, sand, limestone, diatomaceous earth

Abrasives Silicon carbide production Abrasive products fabrication

Sand Tripoli, sandstone

Ceramics, including bricks, tiles, sanitary ware, porcelain, pottery, refractories, vitreous enamels

Mixing, moulding, glaze or enamel spraying, finishing

Clay, shale, flint, sand, quartzite, diatomaceous earth

Iron and steel mills Refractory preparation and furnace repair Refractory materialSilicon and ferro-silicon Raw materials handling SandFoundries (ferrous and non-ferrous)

Casting, shaking out Abrasive blasting, fettling Furnace installation and repair

Sand Sand Refractory material

Metal products including structural metal, machinery, transportation equipment

Abrasive blasting Sand

Shipbuilding and repair Abrasive blasting SandRubber and plastics Raw material handling Fillers (tripoli, diatomaceous

earth)Paint Raw materials handling Fillers (tripoli, diatomaceous

earth, silica flour)Soaps and cosmetics Abrasive soaps, scouring powders Silica flourAsphalt and roofing felt Filling and granule application Sand and aggregate, diatomaceous

earthAgricultural chemicals Raw material crushing, handling Phosphate ores and rockJewellery Cutting, grinding, polishing, buffing Semiprecious gems or stones,

abrasivesDental material Sandblasting, polishing Sand, abrasivesAutomobile repair Abrasive blasting SandBoiler scaling Coal-fired boilers Ash and concretionsFrom IARC, 1997


than in 1979–87: general contractor industry (0.057 mg/m3 versus 0.354 mg/m3), bridge-tunnel construction industry (0.069 mg/m3 versus 0.383 mg/m3), and stonework masonry industry (0.065 mg/m3 versus 0.619 mg/m3). Silica exposures in the grey-iron industry also declined by up to 54% for some occupations (e.g. the geometric mean for “furnace operators” in 1979–87 was 0.142 mg/m3 versus 0.066 mg/m3 in 1988–2003). [The Working Group noted that exposure levels may not have decreased globally.]

Table 1.3 presents the more recent studies that assessed the levels of respirable crystalline silica in a range of industries and countries. Other recent exposure studies that did not measure the respirable crystalline silica components are presented below.

(b) Mines

As part of a cohort mortality study follow-up in four tin mines in China, Chen et al. (2006) developed quantitative exposure estimates of silica mixed dust. Workers in the original cohort were followed up from the beginning of 1972 to the end of 1994. Cumulative exposure estimates were calculated for each worker using their mine employment records and industrial hygiene measurements of airborne total dust, particle size, and free silica content collected since the 1950s. Total dust concentrations of the main job titles exposed were found to have declined from about 10–25 mg/m3 in the beginning of the 1950s to about 1–4 mg/m3 in the 1980s and 1990s. The respirable fraction of total dust was estimated to be 25 ± 4%, and the respirable crystalline silica concentration was estimated to be 4.3% of the total mixed mine dust

Tse et al. (2007) conducted a cross-sectional study to investigate the prevalence of accelerated silicosis among 574 gold miners in Jiangxi, China. Using occupational hygiene data abstracted from government documents and bulk dust data from a study in another gold mine in the region, the estimated mean concentration of respirable

silica dust were reported as 89.5 mg/m3 (range, 70.2–108.8 mg/m3). According to government documents, the total dust concentration in underground gold mining was in the range of 102.6–159 mg/m3 (average, 130.8 mg/m3), and the fraction of silica in total dust was around 75.7–76.1%. No data on the proportion of respir-able dust were available.

To determine dose–response relationships between exposure to respirable dust and respira-tory health outcomes, Naidoo et al. (2006) used historical data (n = 3645) and current meas-urements (n = 441) to characterize exposure to respirable coal mine dust in three South African coal mines. Jobs were classified into the following exposure zones: face (directly involved with coal extraction), underground backbye (away from the coal mining face), and work on the surface. Based on the 8-hour full-shift samples collected respectively, mean respirable dust concentrations in Mines 1, 2, and 3, were as follows: 0.91 mg/m3 (GSD, 3.39; mean silica content, 2.3%; n = 102), 1.28 mg/m3 (GSD, 2.11; mean silica content, 1.4%; n = 63), and 1.90 mg/m3 (GSD, 2.23; mean silica content, 2.7%; n = 73) at the face; 0.48 mg/m3 (GSD, 2.97; mean silica content, 1.48%; n = 30), 0.56 mg/m3 (GSD, 3.71; mean silica content, 1.35%; n = 47), and 0.52 mg/m3 (GSD, 4.06; mean silica content, 0.9%; n = 41) in the backbye zone; and, 0.31 mg/m3 (GSD, 3.52; mean silica content, 0.95%; n = 8), 0.15 mg/m3 (GSD, 3.56; n = 6), and 0.24 mg/m3 (GSD, 7.69; mean silica content, 0.64%; n = 11) in the surface zone. Based on the historical data, overall geometric mean dust levels were 0.9 mg/m3 (GSD, 4.9), 1.3 mg/m3 (GSD, 3.3), and 0.5 mg/m3 (GSD, 5.6) for Mines 1, 2, and 3, respectively.

(c) Granite-quarrying and -processing, crushed stone, and related industries

Bahrami et al. (2008) described the personal exposure to respirable dust and respirable quartz in stone-crushing units located in western Islamic Republic of Iran. A total of 40 personal samples

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Table 1.3 Respirable crystalline silica concentrations in various industries worldwide

Reference, industry and country, period (if reported)

Site, occupation, or exposure circumstance

Concentration of respirable crystalline silica (mg/m3)

Number of samples

Comments

MinesHayumbu et al. (2008), copper mines, the Zambia

Arithmetic mean (SD; range)

Cross-sectional dust exposure assessment; bulk and personal respirable samples; NIOSH method 0600 for gravimetric analysis of respirable dust; NIOSH method 7500 for quartz analysis of bulk and respirable samples; mean personal sampling time: 307 minutes (Mine 1) and 312 minutes (Mine 2)

Mine 1 0.14 (0.2; 0–1.3) 101Mine 2 0.06 (0.06; 0–0.3) 102

Weeks & Rose (2006), metal and non-metal mines, USA, 1998–2002

Arithmetic mean (GM)

Mine Safety and Health Administration compliance data from 4726 mines; 8-hour full-shift personal air samples; gravimetric analysis of respirable dust; NIOSH method 7500 for silica analysis; arithmetic and geometric mean exposure calculated and classified by occupation, mine, and state

Strip and open pit mines 0.047 (0.027) 13702Mills or preparation plants 0.045 (0.027) 1145Underground mines 0.050 (0.029) 1360Overall 0.047 (0.027) 16207

Bråtveit et al. (2003) underground small-scale mining, United Republic of Tanzania, 2001

Geometric mean (GSD)

Personal dust sampling (respirable and total dust) on 3 consecutive day shifts; sampling time varied between 5 and 8 hours; gravimetric analysis of respirable and total dust; NIOSH method 7500 for silica analysis

Drilling, blasting, and shovelling 2.0 (1.7) 6Shovelling and loading of sacks 1.0 (1.5) 3Overall 1.6 (1.8) 9

Park et al. (2002) diatomaceous earth mining and milling, California, USA, 1942–94

Mines and mills Arithmetic mean 0.29 Cumulative exposure (mg/m3–yr) 2.16

NR Re-analysis of data from a cohort of 2342 California diatomaceous earth workers; mean concentration of respirable crystalline silica averaged over years of employment of cohort; crystalline silica content of bulk samples varied from 1–25%, and depended on process location

Mamuya et al. (2006) underground coal mining, United Republic of Tanzania; June–August 2003 and July–August 2004


Personal dust samples collected during two periods in 2003 and 2004; 134 respirable dust samples collected and analysed gravimetrically; 125 samples analysed for quartz using NIOSH method 7500

Development team 0.073 (11.1) 56Mine team 0.013 (2.97) 45Transport team 0.006 (1.84) 11Maintenance team 0.016 (11.05) 13Overall 0.027 (8.18) 125

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Number of samples

Comments

Granite-quarrying and -processing, crushed stone, and related industriesWickman & Middendorf (2002) Granite–quarrying, Georgia, USA; May 1993–February 1994

Arithmetic mean (SD)

Exposure assessment surveys in 10 granite sheds to measure compliance; full-shift respirable dust samples in workers’ breathing zone and area samples; gravimetric analysis of respirable dust; crystalline silica analysis using OSHA ID 142; TWA exposures calculated

Granite sheds 0.052 (0.047) 40

Brown & Rushton (2005a) Industrial silica sand, United Kingdom, 1978–2000

Unadjusted geometric mean (GSD)

Samples collected by companies as part of routine monitoring programme; gravimetric analysis; silica content measured by Fourier transform infrared spectrophotometry until 1997 and by X-ray diffraction thereafter; personal and static measurements combined into one data set

Quarries 0.09 (3.9) 2429 (personal) 583 (static)

Gottesfeld et al. (2008) Stone–crushing mills, India, 2003 (initial phase), 2006 and 2007 (post-implementation of engineering controls)


Bulk and personal air samples collected; silica analysis using NIOSH method 7500; NIOSH method 0500 for respirable particulates used in 2003Prior to water-spray controls (2003) Cristobalite, 0.09

(0.08)[5]

Quartz, 0.25 (0.12)

[5]

After water-spray controlsMonsoon season (winter 2007) Cristobalite, 0.02

(0.01)[18]

Quartz, 0.01 (0.01)

[18]

Dry season (summer 2006) Cristobalite, 0.03 (0.03)

[27]

Quartz, 0.06 (0.12(

[27]

Yingratanasuk et al. (2002) Stone carvers, Thailand, 1999–2000

Arithmetic mean 148 (total number of samples)

Cross-sectional study design; full-shift (8-hour) personal dust samples; respirable dust analysed gravimetrically; silica analysis by infrared spectrophotometry

Carvers (Site 1) 0.22Pestle makers (Site 1) 0.05Mortar makers (Site 2) 0.05Mortar makers (Site 3) 0.88

Table 1.3 (continued)


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Number of samples

Comments

Rando et al. (2001) Industrial sand industry, North America, 1974–98

Geometic mean Exposure estimates created for a longitudinal and case-referent analysis of a cohort of industrial sand workers; gravimetric analysis of total dust; silica analysis by X-ray diffraction spectroscopy

Sand-processing plants 0.042 (overall) 14249

Yassin et al. (2005) Stonework masonry, USA, 1988–2003


Analysis of personal silica measurements (n = 7209) in OSHA IMIS; samples collected using OSHA method ID 142 during 2512 compliance inspectionsAll occupations 0.065 (0.732) 274

FoundriesAndersson et al. (2009) Iron foundry, Sweden, April 2005–May 2006


Respirable dust, quartz, cristobalite, trydimite samples collected on 2 consecutive workdays for shift and daytime workers; gravimetric analysis conducted using modified NIOSH method; respirable quartz and cristobalite analysed using modified NIOSH method 7500

Caster 0.020 (1.8) 22Core Maker 0.016 (2.3) 55Fettler 0.041 (2.9) 115Furnace and ladle repair 0.052 (3.7) 33Maintenance 0.021 (2.6) 26Melter 0.022 (2.0) 49Moulder 0.029 (2.6) 64Sand mixer 0.020 (2.3) 14Shake out 0.060 (1.7) 16Transportation 0.017 (2.6) 13Other 0.020 (2.0) 28All occupations 0.028 (2.8) 435


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Number of samples

Comments

Yassin et al. (2005) Grey–iron foundry, USA 1988–2003


Analysis of personal silica measurements (n = 7 209) in OSHA IMIS; samples collected using OSHA method ID 142 during 2512 compliance inspectionsSpruer 0.154 (0.100) 22

Hunter operator 0.093 (1.144) 10Charger 0.091 (0.999) 8Core maker 0.078 (1.033) 89Grinder 0.075 (0.821) 371Molder 0.073 (0.910) 308Abrasive blast operator 0.070 (0.821) 56Sorter 0.067 (0.827) 23Reline cupola 0.067 (0.725) 29Furnace operator 0.066 (0.766) 47Core setter 0.066 (0.671) 23Craneman 0.066 (0.815) 16Cleaning department 0.060 (0.879) 36Inspector 0.057 (1.298) 21Ladle repair 0.055 (0.829) 30

Other metallurgical operationsFøreland et al. (2008) Silicon carbide industry, Norway, November 2002–December 2003

Geometric mean 720 (total) Exposure survey conducted in 3 silicon carbide plants; measurements collected to improve previously developed job–exposure matrix; sampling duration close to full shift (6–8 hours); 2 sampling periods of 2 work weeks; gravimetric analysis of respirable dust; silica analysis using modified NIOSH method 7500

Cleaning operators (Plant A) 0.020 (quartz)Mix operators (Plants A and C), charger/ mix and charger operators (Plant C)

0.008–0.013 (quartz)

All other jobs (Plants A, B and C) < 0.005 (quartz)Charger/mix operators (Plant C) 0.038

(cristobalite)ConstructionTjoe-Nij et al. (2003) Construction, the Netherlands


Cross-sectional study design; repeated dust measurements (n = 67) on 34 construction workers; full-shift (6–8 hours) personal respirable dust sampling; gravimetric analysis of respirable dust; silica analysis by infrared spectroscopy (NIOSH method 7602); 8-h TWA concentrations calculated

Concrete drillers and grinders 0.42 (5.0) 14

Tuck pointers 0.35 (2.8) 10

Demolition workers 0.14 (2.7) 21



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Number of samples

Comments

Akbar-Khanzadeh & Brillhart (2002) Construction, USA


Task-specific silica exposure assessment conducted as part of an OSHA Consultation Service in Ohio; gravimetric analysis of respirable samples using NIOSH method 0600; silica analysis using in-house method based on NIOSH method 7500 and OSHA ID 142

Concrete–finishing (grinding) 1.16 (1.36) 49

Verma et al. (2003) Range (min–max)

Task-based exposure assessment conducted as part of an epidemiological study of Ontario construction workers; personal dust sampling and direct–reading particulate monitoring; gravimetric analysis of respirable dust using modified NIOSH method 0600; respirable silica analysis using modified NIOSH method 7500

Labourers 0.10–0.15 20Operating engineers 0.04–0.06 3Carpenters, iron workers, masons, painters, terrazzo workers

below detectable limits

17

Woskie et al. (2002) Heavy and highway construction, USA


Personal samples collected using the Construction Occupational Health Program sampling strategy; particulate samples analysed gravimetrically; quartz analysed by Fourier transform infrared spectrophotometry; duration of sampling—6 hours of an 8-hour working day

Labourers 0.026 (5.9) 146

Miscellaneous trade 0.013 (2.8) 26

Operating engineers 0.007 (2.8) 88

Flanagan et al. (2003) Construction, USA, August 2000–January 2001


Respirable samples analysed gravimetrically using NIOSH method 0600; silica analysed by Fourier transform infrared spectrophotometry using NIOSH method 7602Clean-up, demolition with hand-

held tools, concrete cutting, concrete mixing, tuck-point grinding, surface grinding, sacking and patching concrete, and concrete-floor sanding

0.11 (5.21) 113

Lumens & Spee (2001) Construction, the Netherlands


Personal air samples collected during field study at 30 construction sites; duration of sampling 3 to 4 hours; gravimetric analysis of respirable dust samples; silica analysis using NIOSH method 7500

Recess miller 0.7 (3.3) 53Demolition worker 1.1 (4.0) 82Inner wall constructor 0.04 (2.6) 36Overall 0.5 (5.6) 171


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Number of samples

Comments

Flanagan et al. (2006) Construction, USA, 1992–2002


Personal silica measurements collected as part of a silica-monitoring compilation project; data provided by 3 federal or state regulatory agencies (n = 827 samples), 6 university or research agencies (n = 491), and 4 private consultants or contractors (n = 134)

Abrasive blasters, surface and tuck point grinders, jackhammers, rock drills

0.13 (5.9) 1374

Akbar-Khanzadeh et al. (2007) Construction, USA

Arithmetic mean Personal samples collected during grinding operations in a controlled field laboratory to evaluate the effectiveness of wet grinding and local exhaust ventilation; samples collected and analysed using NIOSH methods 0600 and 7500

Uncontrolled conventional grinding

61.7 5 sessions

Wet grinding 0.896 7 sessionsLocal exhaust ventilation grinding 0.155 6 sessions

Bakke et al. (2002) Construction, Norway, 1996–99


Personal samples collected as part of exposure survey; sampling duration: 5 to 8 h; respirable dust analysed gravimetrically; silica analysed by NIOSH method 7500Tunnel workers α-Quartz, 0.035

(5.0)299

Linch (2002) Construction, USA, 1992–98

TWA (8-hour) Personal samples collected as part of NIOSH effort to characterize respirable silica exposure in construction industry; respirable dust collected and analysed according to NIOSH method 0600; silica analysed by NIOSH method 7500

Abrasive blasting of concrete structures

2.8

Drilling concrete highway pavement

3.3

Concrete-wall grinding 0.26Concrete sawing 10.0Milling of asphalt 0.36

Meijer et al. (2001) Construction, USA, 1992–93

Arithmetic mean Personal samples of respirable dust and silica; gravimetric analysis of respirable dust; silica analysed by infrared spectrophotometryConcrete workers 0.06 96

Miscellaneous operationsHicks & Yager (2006) Coal-fired power plants, USA

Arithmetic mean Personal breathing zone samples collected during normal full shifts and analysed by NIOSH method 7500

Normal production activities 0.048 108



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Number of samples

Comments

Shih et al. (2008) Furnace relining, Taiwan, China

Arithmetic mean Exposures measured in a municipal waste incinerator during annual furnace relining; respirable dust collected and analysed by NIOSH method 0600; silica analysed by NIOSH method 7500

Sandblasting 0.578 7Bottom-ash cleaning 0.386 8Wall demolishing 0.116 8Relining 0.041 10Grid repairing 0.042 14Scaffold establishing 0.040 8Others 0.082 8

Zhuang et al. (2001) Pottery factories and metal mines, China, 1988–89

Arithmetic mean Special exposure survey conducted to compare results obtained from traditional Chinese samplers with nylon cyclones; gravimetric analysis of cyclone samples; silica analysis using X-ray diffraction

Pottery factories 0.116 54Iron/copper mines 0.017 23Tin mines 0.097 10Tungsten mines 0.101 56

Yassin et al. (2005) Several industries, USA, 1988–2003


Analysis of personal silica measurements (n = 7 209) in OSHA IMIS; samples collected using OSHA method ID 142 during 2512 compliance inspectionsSoap and other detergents 0.102 (0.757) 6

Testing laboratories services 0.099 (0.896) 53Cut stone and stone products 0.091 (0.956) 405General contractors 0.091 (0.900) 28Coating engraving 0.075 (0.839) 75Grey–iron foundries 0.073 (0.877) 1 760Concrete work 0.073 (0.705) 94Manufacturing explosives 0.070 (0.841) 9Bridge-tunnel construction 0.070 (0.827) 91Stonework masonry 0.065 (0.732) 274Overall 0.073 (0.919) 7209

GM, geometric mean; GSD, geometric standard deviation; IMIS, Integrated Management Information System; NIOSH, National Institute for Occupational Safety and Health; NR, not reported; OSHA; SD, standard deviation



and 40 area samples were collected and analysed by X-ray diffraction. Personal samples were collected after the installation of local exhaust ventilation, and area samples were collected inside the industrial units before (n = 20) and after (n = 20) the installation of local exhaust ventilation. Personal samples were collected from process workers (n = 12), hopper workers (n = 8), drivers (n = 11), and office employees (n = 9). Personal concentrations of respirable dust were as follows: process workers, 0.21 mg/m3; hopper workers, 0.45 mg/m3; and, drivers, 0.20 mg/m3. Personal concentrations of respirable quartz were as follows: process workers, 0.19 mg/m3; hopper workers, 0.40 mg/m3; and, drivers, 0.17 mg/m3. Based on the area samples, the average levels of total dust and respirable dust were 9.46 mg/m3 and 1.24 mg/m3, respectively. The amount of free silica in the stone was 85–97%.

Golbabaei et al. (2004) measured TWA concentrations of total dust, respirable dust, and crystalline silica (α-quartz) in a marble stone quarry located in the north-eastern region of the Islamic Republic of Iran. Full-shift (2 × 4-hour samples) personal breathing zone samples were collected and analysed using gravimetric and X-ray diffraction methods. The highest levels of total and respirable dust exposure were observed for workers in the hammer drill process area (107.9 mg/m3 and 11.2 mg/m3, respectively), and the cutting machine workers had the lowest levels of exposure (9.3 mg/m3 and 1.8 mg/m3, respec-tively). The highest concentrations of α-quartz in total and respirable dust were measured in hammer drill process workers (0.670 mg/m3 and 0.057 mg/m3, respectively).

In a NIOSH-conducted cohort mortality study of workers from 18 silica sand plants, Sanderson et al. (2000) estimated historical quartz exposures using personal respirable quartz measurements (collected during 1974–96) and impinger dust samples (collected in 1946). During 1974–96, a total of 4269 respirable dust samples were collected from workers performing

143 jobs at these 18 plants. Respirable quartz concentrations ranged from less than 1 to 11700 µg/m3, with a geometric mean concen-tration of 25.9 µg/m3. Over one-third of the samples exceeded the Mine Safety and Health Administration permissible exposure limit value for quartz (PEL, 10 mg/m3/(%quartz + 2)), and half of the samples exceeded the NIOSH recommended exposure limit [at the time] (REL, 0.050 mg/m3). Quartz concentrations varied significantly by plant, job, and year and decreased over time, with concentrations meas-ured in the 1970s being significantly greater than those measured later.

(d) Foundries

Lee (2009) reported on exposures to benzene and crystalline silica during the inspection of a foundry processing grey and ductile iron. The facility consisted of two buildings: the main foundry where moulding, core-making, metal pouring, and shakeout took place; and, the finishing part of the site where grinding and painting was done. Personal sampling for crys-talline silica was conducted in the grinding area, in casting shakeout, and in both the mould- and core-making operations. Eight-hour TWA concentrations of crystalline silica were in the range of 2.11–4.38 mg/m3 in the grinding area (n = 4), 1.18–2.14 mg/m3 in the shakeout area (n = 2), and 1.15–1.63 mg/m3 in the core-maker area (n = 2). The 8-hour TWA concentration in the mould area was 0.988 mg/m3.

(e) Construction

In a study of cement masons at six commer-cial building sites in Seattle, WA, USA, Croteau et al. (2004) measured personal exposures to respirable dust and crystalline silica during concrete-grinding activities to assess the effec-tiveness of a commercially available local exhaust ventilation (LEV) system. Levels were measured with and without LEV, one sample directly after the other. A total of 28 paired

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samples were collected. The results showed that the application of LEV resulted in a mean expo-sure reduction of 92%, with the overall geometric mean respirable dust exposure declining from 4.5 to 0.14 mg/m3. However, approximately one quarter of the samples collected while LEV was being used were greater than the OSHA 8–hour TWA PEL (22% of samples), and the American Conference of Governmental Industrial Hygiene (ACGIH) threshold limit value (26%) for respir-able crystalline silica.

Rappaport et al. (2003) investigated exposures to respirable dust and crystalline silica among 80 workers in four trades (bricklayers, painters (when abrasive blasting), operating engineers, and labourers) at 36 construction sites in the Eastern and Midwestern USA. A total of 151 personal respirable air samples were collected and analysed using gravimetric and X-ray diffraction methods. Painters had the highest median exposures for respirable dust and silica (13.5 and 1.28 mg/m3, respectively), followed by labourers (2.46 and 0.350 mg/m3), bricklayers (2.13 and 3.20 mg/m3), and operating engineers (0.720 and 0.075 mg/m3). The following engi-neering controls and workplace characteristics were found to significantly affect silica expo-sures: wet dust suppression reduced labourers’ exposures by approximately 3-fold; the use of ventilated cabs reduced operating engineers’ exposures by approximately 6-fold; and, working indoors resulted in a 4-fold increase in labourers’ exposures.

(f) Agriculture

Archer et al. (2002) assessed the expo-sure to respirable silica of 27 farm workers at seven farms in eastern North Carolina, USA. Four-hour personal breathing zone samples (n = 37) were collected during various agricul-tural activities and analysed for respirable dust, respirable silica, and percentage silica using gravimetric and X-ray diffraction methods. The overall mean respirable dust, respirable silica,

and percentage silica values were 1.31 mg/m3 (n = 37), 0.66 mg/m3 (n = 34), and 34.4% (n = 34), respectively. The highest respirable dust and respirable silica concentrations were measured during sweet potato transplanting (mean, 7.6 and 3.9 mg/m3, respectively; n = 5), and during riding on or driving an uncabbed tractor (mean, 3.1 and 1.6 mg/m3, respectively; n = 13).

Nieuwenhuijsen et al. (1999) measured personal exposure to dust, endotoxin, and crys-talline silica during various agricultural opera-tions at ten farms in California, USA, between April 1995 and June 1996. A total of 142 personal inhalable samples and 144 personal respirable samples were collected. The highest levels of inhalable dust exposure were measured during machine-harvesting of tree crops and vegetables (GM, 45.1 mg/m3 and 7.9 mg/m3, respectively), and during the cleaning of poultry houses (GM, 6.7 mg/m3). Respirable dust levels were generally low, except for machine-harvesting of tree crops and vegetables (GM, 2.8 mg/m3 and 0.9 mg/m3, respectively). The percentage of crystalline silica was higher in the respirable dust samples (overall, 18.6%; range, 4.8–23.0%) than in the inhalable dust samples (overall, 7.4%; range, not detectable to 13.0%).

(g) Miscellaneous operations

Harrison et al. (2005) analysed respirable silica dust samples (n = 47) from several Chinese workplaces (three tungsten mines, three tin mines, and nine pottery mines) to determine the effect of surface occlusion by alumino-silicate on silica particles in respirable dust. The average sample percentages of respirable-sized silica particles indicating alumino-silicate occlusion of their surface were: 45% for potteries, 18% for tin mines, and 13% for tungsten mines.

To provide a more precise estimate of the quantitative relationship between crystalline silica and lung cancer, ‘t Mannetje et al. (2002) conducted a pooled analysis of existing quantita-tive exposure data for ten cohorts exposed to silica

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(US diatomaceous earth workers; Finnish and US granite workers; US industrial sand workers; Chinese pottery workers, and tin and tungsten miners; and South African, Australian, and US gold miners). Occupation- and time-specific exposure estimates were either adopted/adapted or developed for each cohort, and converted to milligrams per cubic metre (mg/m3) respirable crystalline silica. The median of the average cumulative exposure to respirable crystalline silica ranged from 0.04 mg/m3 for US industrial sand workers to 0.59 mg/m3 for Finnish granite workers. The cohort-specific median of cumula-tive exposure ranged from 0.13 mg/m3–years for US industrial sand workers to 11.37 mg/m3–years for Australian gold miners.

In a cross-sectional survey, Hai et al. (2001) determined the levels of respirable nuisance and silica dusts to which refractory brickworkers were exposed at a company in Ha Noi, Viet Nam. Respirable dust levels were in the range of 2.2–14.4 mg/m3 at nine sample sites. The estimated free silica content of dust was 3.5% for unfired materials at the powder collectors (n = 8 samples), and 11.4% in the brick-cleaning area following firing (n = 1 sample).

Burgess (1998) investigated processes asso-ciated with occupational exposure to respirable crystalline silica in the British pottery industry during 1930–1995, and developed a quantitative job–exposure matrix. Exposure estimates were derived from 1390 air samples, the published literature, and unpublished reports of dust control innovations and process changes. In the matrix, daily 8-hour TWA airborne concen-trations of respirable crystalline silica ranged from 0.002 mg/m3 for pottery-support activities performed in the 1990s to 0.8 mg/m3 for firing activities in the 1930s. Although exposure esti-mates within decades varied, median concen-trations for all process categories displayed an overall trend towards progressive reduction in exposure during the 65 year span.

2. Cancer in Humans

2.1 Cancer of the lung

In the previous IARC Monograph (IARC, 1997) not all studies reviewed demonstrated an excess of cancer of the lung and, given the wide range of populations and exposure circumstances studied, some non-uniformity of results had been expected. However, overall, the epidemiological findings at the time supported an association between cancer of the lung and inhaled crystal-line silica (α-quartz and cristobalite) resulting from occupational exposure.

The current evaluation has a primary focus on studies that employed quantitative data on occupational exposures to crystalline silica dust (α-quartz and cristobalite). The establishment of exposure–response relationships not only provides critical evidence of causation, but the availability of quantitative exposures on crys-talline silica and other exposures of relevance facilitates the accurate assessment of exposure–response relationships in the presence of poten-tial confounders. In addition to the focus on quantitative exposure–response relationships, a summary of findings from eight published meta-analyses of lung cancer was also elaborated. Of these, the seven meta-analyses involving absolute risk summarize the information from the many studies that did not consider quantitative expo-sure–response relationships, while the eighth is a meta-analysis of exposure-response.

Findings from cohort studies are given in Table 2.1 available at http://monographs.iarc.fr/ENG/Monographs/vol100C/100C-08-Table2.1.pdf, and those for the case–control studies are provided in Table 2.2 available at http://monographs.iarc.fr/ENG/Monographs/vol100C/100C-08-Table2.2.pdf. Given that there was concern by the previous IARC Working Group that different exposure settings (including the nature of the industry and the crystalline silica polymorph) may give rise to different (or

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http://monographs.iarc.fr/ENG/Monographs/vol100C/100C-08-Table2.1.pdf






no) cancer risks, this evaluation is divided into sections based on the industrial setting where exposure to silica occurs. As with other evalu-ations, data from community-based studies are not included, although studies of persons with silicosis are.

2.1.1 Diatomaceous earth

Work in the diatomaceous earth industry is associated mainly with exposure to cristobalite rather than quartz, and, in the USA, is generally free of other potential confounding exposures apart from exposure to asbestos in a minority of locations. The first study of US diatoma-ceous earth workers revealed significant positive trends in lung cancer risk with both cumulative exposure to crystalline silica (semiquantitative) and duration of employment (Checkoway et al., 1993). Owing to concerns with confounding from asbestos, estimates of asbestos expo-sure were developed (Checkoway et al., 1996). Those with uncertain asbestos exposures were omitted from the analysis leading to the loss of seven lung cancer deaths. Among those with no asbestos exposure, the lung cancer standardized mortality ratios (SMR) for the two higher crystal-line silica exposure groups were twice the magni-tude of those for the two lowest exposure groups, although they were not significantly elevated. Rate ratios, with and without adjustment for asbestos exposure were very similar (within 2%), indicating that confounding due to asbestos was not an issue. Checkoway et al. (1997) provided findings from one of the two plants previously investigated but including 7 more years of follow-up as well as newly developed quantitative respirable crystalline silica exposures (Table 2.1 online). The lung cancer relative risks (RR) for the highest unlagged or 15-year exposure cate-gory were both significantly elevated. Trends for both unlagged and lagged exposure–response were of borderline significance. Rice et al. (2001) used the same cohort to examine risk, assessing

the relationship between lung cancer mortality and respirable crystalline silica exposure using a variety of models. All except one model demon-strated statistical significance, and the trends of the predicted rate ratios with cumulative crystal-line silica exposure were generally similar across models.

A small cohort study among Icelandic diatomaceous earth workers (Rafnsson & Gunnarsdóttir, 1997) provided findings that supported an effect of crystalline silica on lung cancer risk (SIR, 2.34; 95%CI: 0.48–6.85 for those who had worked 5 or more years). Smoking habits among the workers were reported to be similar to the general population.

2.1.2 Ore mining

Steenland & Brown (1995) updated a cohort of US gold miners previously studied (McDonald et al., 1978; Table 2.1 online). Using quantita-tive estimates of cumulative exposure based on particle counts, no obvious evidence of expo-sure–response with lung cancer mortality was observed, nor were any of the exposure category SMRs elevated. In contrast, tuberculosis and silicosis mortality was elevated and exhibited an exposure–response relationship with crystalline silica exposure.

Gold miners were investigated in a South African cohort study (Hnizdo & Sluis-Cremer, 1991) and in case–control studies nested within that cohort study and within another South African gold miner cohort (Reid & Sluis-Cremer, 1996; Tables 2.1 and 2.2 online). In the Hnizdo & Sluis-Cremer, (1991) cohort study, lung cancer mortality was related to cumulative dust expo-sure when modelled as a continuous variable (respirable-surface-area–years) adjusting for smoking, as well demonstrating a monotonic increase with categories of cumulative exposures. There was also some indication of exposure–response in both case–control studies: RR, 1.12; 95%CI: 0.97–1.3 for Reid & Sluis-Cremer (1996),

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and lung cancer mortality was elevated in the highest exposure group adjusting for smoking in the Hnizdo et al. (1997) study. [In this study, exposure to uranium did not confound the results.] [The Working Group noted the potential for confounding from radon, and also noted that the South African cohorts might overlap.]

McLaughlin et al. (1992) undertook a nested case–control study of lung cancer among the members of a prior cohort study by Chen et al. (1992) (Table 2.2 online). The study included workers from iron, copper, tungsten, and tin mines, and used quantitative estimates of crystalline silica dust and certain confounder exposures. Only tin miners showed a clear and substantial exposure–response relationship with the quantitative measures of crystalline silica cumulative exposure. The tin miners underwent further follow-up in a cohort study (Chen et al., 2006) and a nested case–control study (Chen & Chen, 2002). Although the cohort study findings provided some overall indication of elevated lung cancer exposure–response mortality with cumulative dust exposure (Table 2.1 online), the findings were much less clear when presented by mine and silicosis status. In the nested case–control study (Table 2.2 online), there was evidence of exposure–response with cumulative total dust exposures. There was also evidence of a relationship between lung cancer mortality and cumulative arsenic exposure, but the high correlation between arsenic and crystalline silica levels prevented mutual adjustment, and left the etiological factor unclear. The same conclu-sions, more generally expressed, were reported in a simple ever/never exposed approach by Cocco et al. (2001), and were confirmed by Chen et al. (2007) adjusting for smoking and other confounding factors. Here, no relationship of lung cancer mortality with cumulative crystal-line silica exposure was noted for the tungsten mines, nor was any evidence for the iron and copper mines adjusting for radon. [The Working Group noted that crystalline silica exposures

were very low in the iron and copper mines.] For the tin mines, no adjustment for arsenic could be made because of its collinearity with crys-talline silica exposure, but in the overall group, adjusting for smoking, arsenic, polyaromatic hydrocarbons (PAHs), and radon, no exposure–response for cumulative crystalline silica expo-sure emerged either by quintile or through the use of a continuous predictor. This was especially true when the iron/copper mines were removed for reason of having poorer data, when the trend tended towards lower risk with increasing crys-talline silica exposure.

Carta et al. (2001) examined 724 compensated silicotics with radiographic indication of 1/0 or greater small opacities on the International Labor Organization scale who had worked at Sardinian lead and zinc mines, brown coal mines, and granite quarries. Using quantitative estimates of cumulative exposure to respirable crystalline silica dust and radon, the exposure–response was studied in a cohort study and a nested case–control study of 34 lung cancer cases (Tables 2.1 and 2.2 online). Little evidence of a trend with crystalline silica exposure was observed in either study component (after controlling for smoking, airflow obstruction, radon, and severity of sili-cosis in the case–control study). A clear rela-tionship emerged with exposure to radon in the case–control study. [The Working Group noted that this study was small.]

2.1.3 Ceramics

A case–control study of Chinese pottery workers showed evidence of elevated risk for lung cancer with exposure to crystalline silica dust, although no obvious exposure–response was seen in the three higher exposure categories (McLaughlin et al., 1992; Table 2.2 online). This study was nested within the cohort analysis by Chen et al. (1992). Although reported exposure to asbestos was to be minimal, the workers were exposed to PAHs, and in a separate analysis

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there were non-significant elevations in lung cancer risk with increasing cumulative exposure to PAHs. This was confirmed in the follow-up analysis by Chen et al. (2007) that found that the pottery workers had the highest PAH levels over all industrial groups. Adjustment for PAHs in the analysis led to the crystalline silica exposure relative risk of 1.1 (95%CI: 1.02–1.12) dropping to 1.0 (95%CI: 0.96–1.09). [The Working Group noted that in the prior analysis of the Chinese ceramics data by McLaughlin et al. (1992), adjusting for PAHs slightly raised rather than reduced the crystalline silica exposure relative risks. The correlation between the crystalline silica and PAH exposures was reported as 0.56.]

Another case–control study of pottery workers with quantitative crystalline silica dust exposures was from the United Kingdom (Cherry et al., 1998). This analysis, which was restricted to ever smokers but adjusted for smoking amount and ex-smoking, showed a significantly elevated risk of lung cancer mortality with increasing average intensity of exposure, but not with cumulative exposure. No confounders, apart from smoking, were noted in this report.

Ulm et al. (1999) looked at workers in the German ceramics industry, as well as the stone and quarrying industry. The study was based solely on those without silicosis, as assessed using radiographic appearances. No relationship of lung cancer mortality risk with cumulative exposure, average intensity, nor peak exposure was seen in the ceramic worker subset nor overall. [The Working Group noted that the omission of those with silicosis may have restricted the range of crystalline silica exposure in the analysis leading to a loss of power to detect any relation-ship between crystalline silica exposure and lung cancer mortality. Moreover, the modelling included duration of exposure along with cumu-lative exposure, perhaps reducing the ability to detect an effect of crystalline silica exposure.]

2.1.4 Quarries

In an extension of the Vermont granite workers study by Costello & Graham (1988), Attfield & Costello (2004) both lengthened the follow-up from 1982 to 1994, and developed and analysed quantitative crystalline silica dust exposures (Table 2.1 online). The exposures were noteworthy for being developed from environ-mental surveys undertaken throughout the period of the study. However, information on smoking and silicosis status was lacking, although confounding from other workplace exposures was likely to have been minimal or non-existent. The results showed a clear trend of increasing risk of lung cancer mortality with increasing cumulative respirable crystalline silica exposure up until the penultimate exposure group. [The Working Group noted that the findings were heavily dependent on the final exposure group; when it was included, the models were no longer statistically significant.] Graham et al. (2004) undertook a parallel analysis of the same data as Attfield & Costello (2004), but did not use quan-titative exposures, and adopted essentially the same analytical approach as in their 1998 study. They concluded that there was no evidence that crystalline silica dust exposure was a risk factor for lung cancer, their main argument being that lung cancer risks were similar by duration and tenure between workers hired pre-1940 and post-1940 – periods before and following the imposi-tion of dust controls when the crystalline silica dust levels were very different.

As noted above, Ulm et al. (1999) looked at workers in the German stone and quarrying industry (includes some sand and gravel workers), as well as the ceramics industry (Table 2.2 online). The study was based solely on those without sili-cosis, as assessed using radiographic appearances. Neither cumulative exposure, average intensity, nor peak exposure showed a relationship with lung cancer risk in the stone and quarry worker subset, nor overall. [The Working Group noted

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that the omission of those with silicosis may have restricted the range of crystalline silica exposure in the analysis leading to a loss of power to detect any relationship between crystalline silica expo-sure and lung cancer mortality. Moreover, the modelling included duration of exposure along with cumulative exposure, perhaps reducing the ability to detect an effect of crystalline silica exposure.] Another study of German stone and quarry workers found an excess of lung cancer (SMR, 2.40), but no relationship between lung cancer mortality and crystalline silica expo-sure. [The Working Group noted that the cohort study included only 440 individuals with 16 lung cancer cases. It was also restricted to those with silicosis, which was likely to lead to a lack of low exposures, a consequent limited exposure range, and low study power.]

Among studies that did not use quantita-tive estimates of crystalline silica exposure, that by Koskela et al. (1994) is of interest because it reported that the workers had little exposure to possible confounding exposures. The risk of lung cancer was significantly elevated among those with longer duration of exposure and longer latency (P < 0.05). Guénel et al. (1989) also found an excess of lung cancer among stone workers after adjustment for smoking, but this was not the case in a study of slate workers by Mehnert et al. (1990).

2.1.5 Sand and gravel

Confounding from other workplace expo-sures is minimal in sand and gravel opera-tions. There are three main studies of sand and gravel workers, two in North America and one in the United Kingdom. The North American studies appear to arise from the same popula-tion of workers although there is no published information on their overlap, if any. Using the basic information from the McDonald et al. (2001) cohort study of nine North American sand and gravel workers, Hughes et al. (2001)

reported significant exposure–response of lung cancer with quantitative estimates of cumula-tive respirable crystalline silica exposures and other related indices. McDonald et al. (2005) examined a slightly smaller subset of the cohort described by McDonald et al. (2001) based on an extended update at eight of the nine plants, and also undertook a nested case–control study. Risk of lung cancer increased monotonically with unlagged cumulative exposure (P = 0.011), but 15-year lagged cumulative exposures provided a slightly better fit (P = 0.006) (Table 2.2 online). These findings were basically similar to those obtained by Hughes et al. (2001) using the larger cohort and shorter follow-up time. McDonald et al. (2005) reported that average exposure inten-sity, but not years employed, showed a relation-ship with lung cancer risk (P = 0.015).

Steenland & Sanderson (2001) studied workers in 18 sand and gravel companies in the same trade organization as the nine included in the McDonald et al. (2001) study (Table 2.1 online). They, too, employed quantitative esti-mates of exposure derived from company records, and found indications of a relationship with lung cancer mortality, most strongly in the subset that had worked 6 or more months in the industry (P < 0.06). Further analysis using a nested case–control approach found marginal evidence of exposure–response using quartiles of cumulative exposure (P = 0.04), but stronger evidence with average intensity (P = 0.003). [The Working Group noted that a sensitivity analysis of the effect of smoking in this cohort (Steenland & Greenland, 2004) led to an adjusted overall SMR estimate of 1.43 (95% Monte Carlo limits: 1.15–1.78) compared with the original SMR of 1.60 (95%CI: 1.31–1.93). The analysis did not deal with the exposure–response estimates.]

The mortality experience of crystalline silica sand workers in the United Kingdom was evalu-ated by Brown & Rushton (2005b). No overall excess of lung cancer was found (although there was a large, and highly significant, variation

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in lung cancer SMRs between quarries; range: 0.27–1.61, both extremes P < 0.01. Relative risks rose with cumulative respirable crystalline silica dust exposure in the first two quartiles, but fell below 1.0 in the highest quartile, resulting in no trend being detected. [The Working Group noted that Steenland (2005) commented that the low exposures in the Brown & Rushton (2005b) study was likely to have impacted its power to detect a crystalline-silica effect.]

2.1.6 Other industries

Two studies having quantitative exposures to crystalline silica remain, although both indus-tries are known to be associated with exposure to other known or suspected lung carcinogens. The first, by Watkins et al. (2002) was a small case–control study focused on asphalt fumes and crystalline silica exposure. Crystalline silica exposures were low compared to most other studies, and there were no significant lung cancer elevations or trends with exposure (Table 2.2 online). The second study was a nested case–control analysis of Chinese iron and steel workers (Xu et al., 1996). A significant trend with cumulative total dust exposure was reported but not for cumulative crystalline silica dust expo-sure, although the relative risk for the highest crystalline silica-exposed group was elevated. The findings were adjusted for smoking, but not for benzo[a]pyrene exposures, for which the rela-tive risks demonstrated a clear and significant trend with cumulative exposure level.

2.1.7 Semiquantitative exposure and expert-opinion studies

The studies that follow used quantitative exposure measurements in deriving crystalline silica exposure estimates for individuals but ultimately converted them to exposure scores or categories in the epidemiological analysis. Hessel et al. (1986) undertook a case–control study of lung cancer and cumulative crystalline silica

exposure in South African gold miners after coding the dust measurements to four discrete levels (0, 3, 6, 12). No exposure–response was detected. Neither was any evidence of exposure–response detected in the later necropsy study of South African gold miners (Hessel et al., 1990) that used the same approach to code the expo-sure data. [The Working Group noted that the study methods in the case–control study may have led to overmatching for exposure in the case–control study, and that there may have been some selection bias and exposure misclassifica-tion in the second study.]

de Klerk & Musk (1998) undertook a nested case–control analysis of lung cancer within a cohort study of gold miners and showed expo-sure–response for log of cumulative exposure (exposure-score–years) but not for any other index of exposure. The analysis adjusted for smoking, bronchitis, and nickel exposures, and took account of asbestos exposure. The study by Kauppinen et al. (2003) on road pavers found a relative risk for lung cancer of 2.26 in the highest exposure group, but there was no evidence of a linear trend of risk with level of exposure. No adjustment was made for concomitant expo-sures to PAHs, diesel exhaust, and asbestos, nor smoking. Moulin et al. (2000) conducted a nested case–control study to examine lung cancer among workers producing stainless steel and metallic alloys. Their results on 54 cases and 162 controls, adjusted for smoking but not for other confounders, indicated a marginally significant evidence of a trend with increasing crystalline silica exposure as well as with PAH exposure.

Two population-based studies that involved substantial expert opinion in assigning dust levels in developing quantitative crystalline silica exposures Brüske-Hohlfeld et al. (2000) and Pukkala et al. (2005) showed an increasing risk of lung cancer with increasing crystalline silica exposure after adjustment for smoking, and in the latter study, also for social class and exposure to asbestos.

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2.1.8 Pooled analysis, meta-analyses, and other studies

Steenland et al. (2001) reported on a case–control analysis nested within a pooled study of data from ten cohorts from a variety of indus-tries and countries (Table 2.2 online). It included information on diatomaceous, granite, industrial sand, and pottery workers, and workers in tung-sten, tin, and gold mines. Results from all of the studies had been previously published, although not all had originally employed quantitative esti-mates of crystalline silica exposure; and for half, the duration of follow-up had been extended. All indices of cumulative crystalline silica exposure (cumulative, unlagged and lagged; log cumula-tive, unlagged and lagged) showed highly signifi-cant trends with lung cancer risk (P < 0.0001), and average exposure demonstrated a less significant trend (P < 0.05). Of these indices, log cumulative exposure led to homogeneity in findings across the cohorts (P = 0.08 and 0.34 for unlagged and 15-year lag respectively). Findings were similar for the mining and non-mining subgroups. No adjustment was made for smoking and other confounders, although it was noted that smoking had previously been shown not to be a major confounder in five of the ten studies. Analyses of subsets of the data omitting cohorts with suspected other confounders (radon in South African gold mines, and arsenic or PAHs in Chinese tin miners and pottery workers) did not change the overall findings. [The Working Group noted that the robustness in the findings to exclusion of cohorts with potential confounders from other occupational exposures indicates that any confounding in the individual studies were unlikely to have had an impact on their findings related to crystalline silica.]

The presence of silicosis in an individual is a biomarker of high exposure to crystalline silica dust. Accordingly, studies of individuals with silicosis have the potential to provide useful information on the lung cancer risk associated

with exposure to crystalline silica. Three meta-analyses have focused on the risk of lung cancer among individuals with silicosis (Smith et al., 1995; Tsuda et al., 1997; Lacasse et al., 2005). Erren et al. (2009) also provide summary information in an electronic supplement to their article. Four others have looked at crystalline silica exposure (including silicosis status unknown and those without silicosis; Steenland & Stayner, 1997; Kurihara & Wada, 2004; Pelucchi et al., 2006; Erren et al., 2009). The number of studies included ranged from 11 in a meta-analysis focused on individuals without silicosis (Erren et al., 2009) to 43 (Pelucchi et al., 2006) in a study of those with and without silicosis. Reasons for this vari-ation included: the publication date, the time period of interest, whether the study was focused on those with or without silicosis, the originating country of the studies, and analysis-specific criteria. For example, Steenland & Stayner (1997) rejected studies of miners and foundry workers on the assumption that they had the greatest potential for confounding exposures, and Smith et al. (1995) rejected certain studies they deemed under or overestimated the risk of lung cancer. Overall, of the total of 112 publications included by one or more of the seven meta-analyses, none were common to all analyses.

The detailed results from the seven meta-analyses are shown in Table 2.3 available at http://monographs.iarc.fr/ENG/Monographs/vol100C/100C-08-Table2.3.pdf. In brief, all analyses except for those devoted to categories without silicosis found an elevated lung cancer risk, whether occurring among those with silicosis or among crystalline-silica-exposed workers, or arising from cohort or case–control studies. [The Working Group noted that studies that restrict their analysis to individuals without silicosis potentially limit their range of crystal-line silica exposure, because individuals with the highest exposures tend to be omitted. Limiting the range of exposure results in reduced power to detect associations.] Overall, the rate ratios were

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very similar across studies (1.74–2.76 for those with silicosis, and 1.25–1.32 for workers exposed to crystalline silica). Results from case–control studies, where there is greater opportunity to control for smoking, revealed lower rate ratios than from cohort studies in two analyses, greater rate ratios in two, and about the same in the fifth (the sixth analysis did not break the results out separately by study type). Moreover, the supple-mentary materials of Erren et al. (2009) show equal risk for crystalline silica exposure in unad-justed and smoking-adjusted studies. The two available analyses providing results on workers exposed to crystalline silica by type of study reported larger rate ratios from the case–control studies.

A further meta-analysis examined exposure–response (Lacasse et al., 2009) rather than overall risk, and for this reason its findings are reported separately. The analysis included findings from ten studies having quantitative measurements of crystalline silica exposure and adjustment for smoking. An increasing risk of lung cancer was observed with increasing cumulative exposure to crystalline silica above a threshold of 1.84 mg/m3 per year. Although the overall findings were heterogeneous, they were similar to those from a subset of seven more homogeneous studies.

Many of the meta-analyses noted that a lung cancer risk was apparent either after adjusting for smoking or among non-smokers (Smith et al., 1995; Tsuda et al., 1997; Kurihara & Wada, 2004; Lacasse et al., 2005). Yu & Tse (2007) further explored the issue of smoking on the interpre-tation of the published cohort and case–control studies of crystalline silica exposure and lung cancer. In this, they examined reported SMRs and standardized incidence ratios (SIR) for lung cancer reported in ten different published studies, and concluded that the risk had been systematically underreported for never smokers. After adjustment, five of the ten SMRs and SIRs showed significant lung cancer excesses among never smokers compared to two when unadjusted,

and ranged from 2.60–11.93. The SMRs and SIRs for ever smokers were reduced after adjustment for smoking, but tended to retain their statistical significance.

2.2 Other cancers

2.2.1 Cancer of the stomach

In the 40 reports with information on cancer of the stomach, 18 had relative risks > 1.0 (including three significantly elevated), and 22 with relatives risks ≤ 1.0 (including two signifi-cantly reduced).

2.2.2 Digestive, gastro-intestinal, or intestinal cancers

In the 15 reports of digestive, gastro-intes-tinal, or intestinal cancer, seven had relative risks > 1.0 (including one significantly elevated), and eight with reltaive risks ≤ 1.0 (two significantly reduced).

2.2.3 Cancer of the oesophagus

In the 14 reports of oesophageal cancer, five had relative risks > 1.0 (including three signifi-cantly elevated), and nine with relative risks ≤ 1.0.

Wernli et al. (2006) reported a hazard ratio of 15.80 (95%CI: 3.5–70.6) among Chinese textile workers exposed for over 10 years to crystalline silica dust. In Chinese refractory brick workers, Pan et al. (1999) found not only a significant elevation with being ever exposed to crystalline silica dust (RR, 2.75; 95%CI: 1.44–5.25), but also a clear exposure–response relationship with years of exposure, adjusting for smoking and other personal factors. [The Working Group noted that confounding from exposure to PAHs could not be ruled out in the above two studies.]

Yu et al. (2007) reported an overall SMR for cancer of the oesophagus of 2.22 (95%CI: 1.36–3.43), and an SMR of 4.21 (95%CI: 1.81–8.30)

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among caisson workers (who were noted to have had higher exposures to crystalline silica dust than non-caisson workers). The relative risk of oesophageal cancer for caisson workers with silicosis was reduced to 2.34 after adjusting for smoking and alcohol drinking. No excess risk of oesophageal cancer was observed among the non-caisson workers with silicosis after adjustment.

2.2.4 Cancer of the kidney

In the eight reports on cancer of the kidney, five had relative risks > 1.0 (including two signifi-cantly elevated), and three with relative risks ≤ 1.0. The two with significantly elevated risks provided information on exposure–response relationships with crystalline silica exposure, although neither formally evaluated this. In US sand and gravel workers (McDonald et al., 2005), a non-significant negative trend with increasing crystalline silica exposure was observed. However, in Vermont granite workers (Attfield & Costello, 2004), kidney cancer SMRs increased almost monotonically with increasing exposure (except for the last exposure group), and the SMR of 3.12 in the penultimate exposure group was significantly elevated.

2.2.5 Others

There have been isolated reports of excesses in other cancers but the evidence is, in general, too sparse for evaluation. Elci et al. (2002) reported an excess of cancer of the larynx in workers potentially exposed to crystalline silica dust, particularly for supraglottic cancer (OR, 1.8; 95%CI: 1.3–2.3), with a significant exposure–response relationship.

2.3 Synthesis

Findings of relevance to lung cancer and crystalline silica exposure arise from five main industrial settings: ceramics, diatomaceous

earth, ore mining, quarries, and sand and gravel. Of these, the industries with the least potential for confounding are sand and gravel operations, quarries, and diatomaceous earth facilities. Among those industry segments, most studies with quantitative exposures report associations between crystalline silica exposure and lung cancer risk. The findings are supported by studies in these industries that lack quantitative expo-sures. Results from the other industry segments generally added support although some studies had potential confounding from arsenic, radon, or PAHs. In one case among Chinese tin miners, the arsenic and crystalline silica exposures were virtually collinear, and no adjustment could be made for arsenic. In another (Chinese pottery workers), adjustment for PAHs removed a signif-icant crystalline silica exposure effect, and in a third, among iron and copper miners, the crys-talline silica effect disappeared after adjustment for radon. In these, the role of crystalline silica exposure must be regarded as unclear. Mixed findings were reported among gold, tungsten, and lead/zinc miners.

The strongest evidence supporting the carci-nogenicity of crystalline silica in the lung comes from the pooled and meta-analyses. The pooled analysis demonstrated clear exposure–response, while all of the meta-analyses strongly confirmed an overall effect of crystalline silica dust expo-sure despite their reliance on different studies in coming to their conclusions.

Cancers other than that of the lung have not been as thoroughly researched. In many cases the findings were reported in passing, in analyses focused on lung cancer, and rarely have the data examined exposure–response with crystalline silica exposure or its surrogates.

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3. Cancer in Experimental Animals

No additional relevant cancer bioassays have been conducted since the previous IARC Monograph (IARC, 1997) except for a study in hamsters by inhalation (Muhle et al., 1998), and a study in mice by intratracheal instillation (Ishihara et al., 2002). Studies from the previous evaluation considered adequate are summarized below together with the new studies published since.

3.1 Inhalation exposure

See Table 3.1

3.1.1 Mouse

Female BALB/cBYJ mice exposed to crystal-line silica by inhalation (Wilson et al., 1986) did not have an increase in lung tumours compared to controls. Pulmonary adenomas were observed in both the silica-exposed (9/60) and the control animals (7/59). [The Working Group noted that the study groups were small (6–16 mice).]

3.1.2 Rat

Male and female F344 rats were exposed to 0 or 52 mg/m3 of crystalline silica (Min-U-Sil) over a 24-month period. Interim removals of ten males and ten females per group were made after 4, 8, 12, and 16 months of exposure. Half of those removed were necropsied, and half were held until the end of the 24 months. None of the controls developed a lung tumour. In the silica-exposed rats, the first pulmonary tumour appeared at 494 days, and the incidence was 10/53 in females and 1/47 in males (Dagle et al., 1986).

One group of 62 female F344 rats was exposed by nose-only inhalation to 12 mg/m3 crystalline silica (Min-U-Sil) for 83 weeks. An equal number of controls was sham-exposed to filtered air, and 15 rats were left untreated. The animals were

observed for the duration of their lifespan. There were no lung tumours in the sham-exposed group, and 1/15 unexposed rats had an adenoma of the lung. In the quartz-exposed rats, the inci-dence of lung tumours was 18/60 (Holland et al., 1983, 1986; Johnson et al., 1987).

Groups of 50 male and 50 female viral antibody-free SPF F344 rats were exposed by inhalation to 0 or 1 mg/m3 silica (DQ12; 87% crystallinity as quartz) for 24 months. The rats were then held for another 6 weeks without exposure. The incidence of lung tumours in the silica-exposed rats was 7/50 males and 12/50 in females. Only 3/100 controls had lung tumours (Muhle et al., 1989, 1991, 1995).

Three groups of 90 female Wistar rats, 6–8 weeks old, were exposed by nose-only inha-lation to 6.1 or 30.6 mg/m3 DQ12 quartz for 29 days. Interim sacrifices were made imme-diately after the exposure and at 6, 12, and 24 months, with the final sacrifice at 34 months after exposure. The total animals with lung tumours was 0 (controls), 37/82 (low dose), and 43/82 (high dose). Many animals had multiple tumours (Spiethoff et al., 1992).

3.1.3 Hamster

Groups of 50 male and 50 female Syrian golden hamsters were exposed to 0 (control) or 3 mg/m3 DQ12 quartz (mass median aerodynamic diam-eter, 1.3 μm) for 18 months. The experiment was terminated 5 months later. In the silica-exposed group, 91% of the animals developed very slight to slight fibrosis in the lung, but no significant increase of lung tumours was observed (Muhle et al., 1998)

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Table 3.1 Studies of cancer in experimental animals exposed to crystalline silica (inhalation exposure)

Species, strain (sex) Duration Reference

Dosing regimen Animals/group at start Particle size, GSD

Incidence of tumours in respiratory tract Significance Comments

Mouse, BALB/c BYJ (F) 150, 300 or 570 d Wilson et al. (1986)

0, 1.5, 1.8 or 2.0 mg/m3 8 h/d, 5 d/wk 6–16 animals Diameter < 2.1 μm

Lung (adenomas): 7/59 (control), 9/60 (all exposed)

[NS]

Rat, F344 (M, F) 24 mo Dagle et al. (1986)

0, 52 mg/m3 6 h/d, 5 d/wk 72/sex MMAD, 1.7–2.5 μm; GSD, 1.9–2.1

Lung (epidermoid carcinomas): M–0/42 (control), 1/47 F–0/47 (control), 10/53

[NS] [P < 0.002]

Rat, F344 (F) Lifespan Holland et al. (1983, 1986); Johnson et al. (1987)

0, 12 mg/m3 6 h/d, 5 d/wk for 83 wk 62 animals MMAD, 2.24 μm; GSD, 1.75

Lung (tumours): 0/54 (control), 18/60 (11 adenocarcinomas, 3 squamous cell carcinomas, 6 adenomas)

[P < 0.001] Nose-only inhalation exposure. Age unspecified

Rat, SPF F344 (M, F) 30 mo Muhle et al. (1989, 1991, 1995)

0, 1 mg/m3 6 h/d, 5 d/wk for 24 mo 50/sex MMAD, 1.3 μm; GSD, 1.8

Lung (tumours): 3/100 (control M, F), 7/50 (M), 12/50 (F) M–1 adenoma, 3 adenocarcinomas, 2 benign cystic keratinizing squamous cell tumours, 1 adenosquamous carcinoma, 1 squamous cell carcinoma F–2 adenomas, 8 adenocarcinomas, 2 benign cystic keratinizing squamous cell tumours

Unspecified (M) [P < 0.05] (F)

Rat, Wistar (F) Up to 35 mo Spiethoff et al. (1992)

0, 6.1, 30.6 mg/m3 6 h/d, 5 d/wk for 29 d 90 animals MMAD, 1.8 μm; GSD, 2.0

0/85 (control), 37/82 (low dose), 43/82 (high dose) Multiple tumours/rat: 21 bronchiolo-alveolar adenomas, 43 bronchiolo-alveolar carcinomas, 67 squamous cell carcinomas, 1 anaplastic carcinoma

[P < 0.0001] (both doses)

Nose-only inhalation exposure

d, day or days; F, female; GSD, geometric standard deviation; h, hour or hours; M, male; MMAD, mass median aerodynamic diameter; mo, month or months; NS, not significant; wk, week or weeks


3.2 Intranasal administration

3.2.1 Mouse

Two groups of 40 female (C57xBALB/c) F1 mice received a single intranasal instillation of 4 mg of synthetic d- or l-quartz. A group of 60 females received an intranasal instillation of saline. Survivors were killed at 18 months after treatment, and the incidence of lymphomas and leukaemias combined was 0/60 (controls), 2/40 (d-quartz), and 6/40 (l-quartz) (Ebbesen, 1991). [The Working Group noted that the study was not designed to detect silica-induced lung tumours, and also noted the lack of information on quartz retention.]

3.3 Intratracheal administration

See Table 3.2

3.3.1 Mouse

A group of 30 male A/J mice, 11–13 weeks old, received weekly intratracheal instillations of 2.9 mg quartz for 15 weeks. A group of 20 mice received instillations of vehicle [unspecified]. Animals were killed 20 weeks after the instilla-tions. The incidences of lung adenomas were 9/29 in the controls, and 4/20 for the silica-instilled mice, values that were not statistically different (McNeill et al., 1990).

Ishihara et al. (2002) administered a single dose (2 mg in saline/mouse) of crystalline silica to a group of four C57BL/6N mice by intratracheal instillation to study subsequent genotoxic effects. A control group of four animals was instilled saline only. Silicotic lesions were observed in the lungs of the exposed mice, but no pulmonary neoplasms were observed after 15 months.

3.3.2 Rat

A group of 40 Sprague Dawley rats [sex unspecified] received weekly instillations of 7 mg quartz (Min-U-Sil) in saline for 10 weeks. Another groups of 40 rats received instillations of saline alone, and 20 rats remained untreated. Animals were observed over their lifespan. The incidence of lung tumours in quartz-treated rats was 6/36, 0/40 in the saline controls, and 0/18 in the untreated rats (Holland et al., 1983).

Groups of 85 male F344 rats received a single intratracheal instillation of 20 mg quartz in deion-ized water, Min-U-Sil or novaculite, into the left lung. Controls were instilled with vehicle only. Interim sacrifices of ten rats were made at 6, 12, and 18 months with a final sacrifice at 22 months. The incidence of lung tumours in the Min-U-Sil-instilled rats was 30/67, in the novaculite-treated rats 21/72, and in controls 1/75. All of the lung tumours were adenocarcinomas, except for one epidermoid carcinoma in the novaculite-treated rats (Groth et al., 1986).

Groups of male and female F344/NCr rats [initial number unspecified] received one intratracheal instillation of 12 or 20 mg quartz in saline or 20 mg of ferric oxide (non-fibrogenic dust) in saline. Interim sacrifices were made at 11 and 17 months with a final sacrifice at 26 months. There was a group of untreated controls observed at unscheduled deaths after 17 months. No lung tumours were observed in the ferric-oxide-treated rats and only one adenoma was observed in the untreated controls. The high incidences of benign and mainly malignant lung tumours observed in the quartz-treated rats is summa-rized in Table 3.3 (Saffiotti, 1990, 1992; Saffiotti et al., 1996).

Six groups of 37–50 female Wistar rats, 15 weeks old, received either a single or 15 weekly intratracheal instillation of one of three types of quartz preparations in saline (see Table 3.4). A control group received 15 weekly instillations of saline. To retard the development of silicosis,

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Table 3.2 Studies of cancer in experimental animals exposed to silica (intratracheal instillation)

Species, strain (sex) Duration Reference

Dosing regimen Animals/group at start Particle size

Incidence of tumours Significance

Mouse, A/J (M) 20 wk McNeill et al. (1990)

0, 2.9 mg Weekly for 15 wk 30, 20 (controls) 1–5 μm (size not further specified)

Lung (adenomas): 9/29 (control), 4/20 Tumour multiplicity: 0.31 ± 0.09 (control), 0.20 ± 0.09

[NS] [NS]

Rat, Sprague Dawley (NR) Lifespan Holland et al. (1983)

0 (saline), 7 mg Weekly for 10 wk 40 animals 1.71 ± 1.86 μm

Lung (1 adenoma, 5 carcinomas): 0/40 (control), 6/36

[P<0.05] (carcinomas)

Rat, F344 (M) 22 mo Groth et al. (1986)

0, 20 mg once only 85 animals < 5 μm

Lung (adenocarcinomas): 1/75 (control), 30/67

[P<0.001]

Rat, F344/NCr (M, F) 11, 17 or 26 mo Saffiotti (1990, 1992); Saffiotti et al. (1996)

0, 12, 20 mg quartz Once only Ferric oxide (20 mg) was negative control [Initial number of rats, NR] 0.5–2.0 μm

High incidences of benign and mainly malignant lung tumours in quartz-treated rats reported in Table 3.3 No tumours observed in ferric oxide group One adenoma in untreated controls

NR

Rat, Wistar Lifespan Pott et al. (1994)

0 (saline), one single or 15 weekly injections of one of 3 types of quartz Some rats received PVNO to protect against silicosis 37–50/group

Incidences of benign and malignant lung tumours in quartz-treated rats are shown in Table 3.4 No tumours observed in saline-treated rats

NR

Hamster Syrian Golden (NR) Lifespan Holland et al. (1983)

0 (saline), 3, 7 mg quartz (Min-U-Sil) Once a wk for 10 wk 48/group; 68 (controls) 1.71 ± 1.86 μm

No lung tumours in any group

Hamster, Syrian Golden (M) Lifespan Renne et al. (1985)

0 (saline), 0.03, 0.33, 3.3, or 6.0 mg quartz (Min-U-Sil) weekly for 15 wk 25–27/group MMAD, 5.1 μm Geometric diameter, 1.0 μm

No lung tumours in any group

Hamster, Syrian Golden (M) 92 wk Niemeier et al. (1986)

0 (saline), 1.1 (Sil-Co-Sil) or 0.7 (Min-U-Sil) mg One group received 3 mg ferric oxide 50/group 5 μm (Min-U-Sil)

No tumours in saline controls or in Sil-Co-Sil groups 1 adenosquamous carcinoma of the bronchi and lung in Min-U-Sil group and 1 benign tumour of the larynx in ferric oxide group

M, male; MMAD, mass median aerodynamic diameter; mo, month or months; NR, not reported; NS, not significant; PVNO, polyvinylpyridine-N-oxide; wk, week or weeks


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Table 3.3 Incidence, numbers, and histological types of lung tumours in F344/NCr rats after a single intratracheal instillation of quartz

Treatment Observation time Lung tumours

Material Dosea Incidence Types

MalesUntreated None 17–26 mo 0/32Ferric oxide 20 mg 11–26 mo 0/15Quartz (Min-U-Sil 5) 12 mg Killed at 11 mo 3/18 (17%) 6 adenomas, 25 adenocarcinomas, 1 undifferentiated carcinoma, 2

mixed carcinomas, 3 epidermoid carcinomasKilled at 17 mo 6/19 (32%)17–26 mo 12/14 (86%)

Quartz (HF-etched Min-U-Sil 5) 12 mg Killed at 11 mo 2/18 (11%) 5 adenomas, 14 adenocarcinomas, 1 mixed carcinomaKilled at 17 mo 7/19 (37%)17–26 mo 7/9 (78%)

FemalesUntreated None 17–26 mo 1/20 (5%) 1 adenomaFerric oxide 20 mg 11–26 mo 0/18Quartz (Min-U-Sil 5) 12 mg Killed at 11 mo 8/19 (42%) 2 adenomas, 46 adenocarcinomas, 3 undifferentiated carcinomas,

5 mixed carcinomas, 3 epidermoid carcinomasKilled at 17 mo 10/17 (59%)17–26 mo 8/9 (89%)

20 mg 17–26 mo 6/8 (75%) 1 adenoma, 10 adenocarcinomas, 1 mixed carcinoma, 1 epidermoid carcinoma

Quartz (HF-etched Min-U-Sil 5) 12 mg Killed at 11 mo 7/18 (39%) 1 adenoma, 36 adenocarcinomas, 3 mixed carcinomas, 5 epidermoid carcinomasKilled at 17 mo 13/16 (81%)

17–26 mo 8/8 (100%)a Suspended in 0.3 or 0.5 mL salineHF, hydrogen fluoride; mo, month or monthsFrom Saffiotti (1990, 1992), Saffiotti et al. (1996)

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Table 3.4 Incidence, numbers, and histological types of lung tumours in female Wistar rats after intratracheal instillation of quartz

Material Surface area

No. of instillations

No. of rats examined

No. and #% of rats with primary epithelial lung tumoursa Other tumoursb

(m2/g) (del # × mg) Adenoma Adenocarcinoma Benign CKSCT

Squamous cell carcinoma

Total (%)

Quartz (DQ 12) 9.4 15 × 3 37 0 1z 11 1 + 1y 38 1Quartz (DQ 12) + PVNO 9.4 15 × 3 38 0 1 + 3z 8 + 1x 4+1x+3y+1z 58 2Quartz (DQ 12) 9.4 1 × 45 40 0 1 7 1 23 2Quartz (Min-U-Sil) – 15 × 3 39 1 4 + 4z 6 1+2y+2z+1y,z 54 3Quartz (Min-U-Sil) + PVNO – 15 × 3 35 1 2 + 1x 8 5+1x+1y+1z 57 3Quartz Sykron (F 600) 3.7 15 × 3 40 0 3 5 3 + 1z 30 10.9% Sodium chloride – 15 × 0.4 mL 39 0 0 0 0 0 5

a If an animal was found to bear more than one primary epithelial lung tumour type, this was indicated as follows:xadenoma; yadenocarcinoma; zbenign CKSCT.b Other types of tumours in the lung: fibrosarcoma, lymphosarcoma, mesothelioma or lung metastases from tumours at other sitesPVNO, polyvinylpyridine-N-oxide; CKSCT, cystic keratinizing squamous cell tumourFrom Pott et al. (1994)


two of the groups received injections of poly-vinylpyridine-N-oxide. All groups of quartz-exposed rats had a significant increase in lung tumours, and the rats protected against silicosis developed more pulmonary squamous cell carci-nomas than rats that were not protected (Pott et al., 1994).

3.3.3 Hamster

Two groups of 48 Syrian hamsters [sex unspec-ified] received intratracheal instillations of 3 or 7 mg quartz (Min-U-Sil) in saline once a week for 10 weeks. A group of 68 hamsters received saline alone, and another group of 72 hamsters were untreated. All animals were observed for their lifespan. No lung tumours were observed in any of the groups (Holland et al., 1983).

Groups of 25–27 male Syrian golden hamsters, 11–weeks old, received weekly intratracheal instillation of 0.03, 0.33, 3.3, or 6.0 mg quartz (Min-U-Sil) in saline for 15 weeks. Groups of 27 saline-instilled hamsters and 25 untreated controls were used as controls. Animals were observed for their lifespan. No lung tumours were observed in any group (Renne et al., 1985).

Three groups of 50 male Syrian golden hamsters received weekly instillations of 1.1 mg of quartz as Sil-Co-Sil, or 0.7 mg of quartz as Min-U-Sil, or 3 mg of ferric oxide (non-fibro-genic particle) in saline for 15 weeks. A group of 50 saline-instilled hamsters served as controls. Survivors were killed at 92 weeks after the begin-ning of the instillations. No respiratory tract tumours were observed in the hamsters exposed to Sil-Co-Sil or in the saline controls. One aden-osquamous carcinoma of the bronchi and lung was observed in the Min-U-Sil group, and one benign tumour of the larynx in the ferric-oxide-exposed group (Niemeier et al., 1986).

3.4 Intrapleural and intrathoracic administration

3.4.1 Mouse

One mouse study was reported in the previous IARC Monograph (IARC, 1997) in which the route of exposure was via a single intrathoracic injec-tion of tridymite. The study was only reported as an abstract, and therefore is not described here (Bryson et al., 1974).

3.4.2 Rat

Two groups of 48 male and 48 female standard Wistar rats and two groups 48 male and 48 female SPF Wistar rats were given a single intrapleural injection of 20 mg alkaline-washed quartz (size, < 5 μm) in saline, and observed for their lifespan. Control rats received injections of 0.4 mL saline alone. Malignant tumours of the reticuloendothelial system involving the thoracic region were observed in 39/95 quartz-treated SPF rats [P < 0.001] (23 histiocytic lymphomas, five Letterer-Siwe/Hand-Schüller-Christian disease-like tumours, one lymphocytic lymphoma, four lymphoblastic lymphosarcomas, and six spindle cell sarcomas), and in 31/94 quartz-treated standard rats [P < 0.001] (30 histiocytic lymphomas and one spindle-cell sarcoma). In the SPF control animals, 8/96 rats had tumours (three lymphoblastic lymphosarcomas, five retic-ulum cell sarcomas), 7/85 standard rat controls had tumours (one lymphoblastic lymphosar-coma, and six reticulum cell sarcomas) (Wagner & Berry, 1969; Wagner, 1970; Wagner & Wagner, 1972). [The Working Group noted that the distri-bution of tumours over sexes was unspecified.]

In a second study, with the same dosing regimen and type of quartz, 23 rats developed malignant reticuloendothelial system tumours (21 malignant lymphomas of the histiocytic type [MLHT], two thymomas, and one lymphosar-coma/thymoma/spindle cell sarcoma) in 80 male

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and 80 female SPF Wistar rats after 120 weeks. In another experiment, 16 male and 16 female SPF Wistar rats dosed similarly with Min-U-Sil quartz were observed until they were moribund. Eight of the 32 rats developed MLHT and three developed thymomas/lymphosarcomas. In a last experiment with the same experimental design, 18 of 32 SPF Wistar rats that had been injected with cristobalite developed malignant lymphomas (13 MLHT and five thymomas/lymphosarcomas). No MLHT and one thymoma/lymphosarcoma tumours were observed in 15 saline-injected control rats. (Wagner, 1976). [The Working Group noted that the distribution of tumours over sexes was unspecified, and that no statistics were provided.]

In one experiment, groups of 16 male and 16 female Wistar rats were given intrapleural injec-tions of 20 mg of four types of quartz (Min-U-Sil, D&D, Snowit, and DQ12). The animals were observed for their lifespan. For all but the group treated with DQ12 quartz, there was a statisti-cally significant increase in MLHT over saline controls (Table 3.5). In a second experiment with the same experimental design, two other strains of rats were injected Min-U-Sil (12 male and 12 female PVG rats and 20 male and 20 female Agus rats). A non-significant increase in MLHT was observed in both strains, and there was no MLHT in the saline controls. In a third experi-ment with the same experimental design, cristo-balite was injected, and 4/32 treated Wistar rats developed MLHT [not significant], but none of the 32 saline controls did. In a final experiment, 16 male and 16 female Wistar rats were injected triolymite (size, < 0.5 μm; 0.35x106 particle/μg), and observed for their lifespan. A total of 16/32 Wistar rats developed MLHT, whereas no such tumours were observed in the 32 saline controls (Wagner et al., 1980). [The Working Group noted that the distribution of tumours over sexes was unspecified.]

Two groups of 36 2-month-old male Sprague-Dawley rats, received a single

intrapleural injection of 20 mg DQ12 quartz in saline or saline alone, and were observed for their lifespan. Twenty-seven male rats served as untreated controls. Six malignant histiocytic lymphomas and two malignant Schwannomas were observed in the quartz-treated group [not significant], and one chronic lymphoid leukaemia and one fibrosarcoma were observed in the saline group and untreated controls, respectively (Jaurand et al., 1987).

3.5 Intraperitoneal administration

3.5.1 Rat

Two groups of 16 male and 16 female SPF Wistar rats received a single intraperitoneal injection of 20 mg of Min-U-Sil quartz in saline, and were observed for their lifespan. There were 12 saline controls [sex unspecified]. A total of 9/64 quartz-exposed rats developed malignant lymphomas (two MLHT and seven thymoma/lymphosarcomas). None of the saline controls developed MLHT, but one thymoma/lymphosar-coma was noted (Wagner, 1976). [The Working Group noted that the distribution of tumours over sexes was unspecified.]

3.6 Subcutaneous administration

3.6.1 Mouse

Two groups of 40 female (C57xBALB/c) F1 mice received a single subcutaneous injection of 4 mg of d- or l-quartz. A group of 60 female mice served as saline controls. At 18 months after injection, there was an incidence of lymphomas/leukemias of 0/60, 1/40 and 12/40 (P < 0.001), and of liver adenomas of 0/60, 1/40 and 3/40 for the saline controls, d-quartz and l-quartz groups, respectively. No injection-site tumours were reported (Ebbesen, 1991).

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3.7 Intravenous administration

3.7.1 MouseGroups of 25 male and 25 female strain A

mice were injected in the tail vein with 1 mg quartz in 0.1 mL of saline, with a control group of 75 male and female untreated animals. Animals were killed 3, 4.5 or 6 months after injection. There was no difference in the incidences and multiplicities of pulmonary adenomas between treated and untreated animals (Shimkin & Leiter, 1940).

3.8 Administration with known carcinogens

3.8.1 Inhalation

(a) Rat

Studies have been completed to determine the effect of co-exposure to silica and Thorotrast, a known carcinogen (See Table 3.6). Two sets of three groups of 90 female Wistar rats, 6–8 weeks old, were exposed by inhalation to 0, 6, or 31 mg/m3 of DQ12 quartz (mass median diameter, 1.8 µm; GSD, 2.0) for 6 hours/day 5 days/week for 29 days. One week after the inhalation exposure,

one group of quartz-exposed rats and one group of sham-exposed rats received an intravenous injection of Thorotrast (2960 Bq 228Th/mL, 0.6 mL). Controls were only sham-exposed. In each of the six groups, interim sacrifices of three or six animals each were made 0, 6, 12 and 24 months after the end of exposure. The experi-ment was terminated 34 months after the end of exposure. In rats that were exposed to silica by inhalation and then given Thorotrast, there was a small increase in lung tumours compared to the already high incidence of benign and malignant tumours induced by silica alone (Spiethoff et al., 1992).

3.8.2 Intratracheal administration

(a) Rat

Four groups of white rats (group sizes varied from 28 to 70, with approximately equal numbers of males and females) were given either no treat-ment or a single instillation of 5 mg benzo[a]pyrene or an instillation of 50 mg quartz (size, 82% < 2 μm) and 5 mg benzo[a]pyrene (Group A) or 50 mg quartz and a later (1 month) instil-lation of 5 mg benzo[a]pyrene (Group B). The rats were observed until death. There were no

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Table 3.5 Incidences of malignant lymphoma of the histiocytic type (MLHT) in Wistar rats after an intrapleural injection of 20 mg quartz/animal

Sample No. of particles × 106/μg

Size distribution (%) Mean survival (days)

Incidence of MLHT (%)a

< 1 μm 1–2 μm 2–4.6 μmMin-U-Sil (a commercially prepared crystalline quartz probably 93% pure)

0.59 61.4 27.9 9.1 545 11/32 (34%)b

D&D (obtained from Dowson & Dobson, Johannesburg, pure crystalline quartz)

0.30 48.4 33.2 18.4 633 8/32 (25%)b

Snowit (commercially prepared washed crystals)

1.1 81.2 12.9 5.6 653 8/32 (25%)b

DQ12 (standard pure quartz) 5.0 91.4 7.8 0.8 633 5/32 (16%)Saline controls – – – – 717 0 [0/32] (0%)

a Sex unspecifiedb [Significantly different from controls by Fisher Exact test,P < 0.05]From Wagner et al. (1980)


lung tumours in the untreated rats (0/45), nor in those exposed to benzo[a]pyrene alone (0/19). In the combined exposures to benzo[a]pyrene and quartz, an increased incidence in lung tumours was observed (Group A, 14/31, 11 squamous cell carcinomas and three papillomas; Group B, 4/18, two papillomas and two carcinomas) (Pylev, 1980). [The Working Group noted the absence of a group exposed to quartz alone.]

(b) Hamster

Groups of 50 male Syrian golden hamsters received weekly intratracheal instillations for 15 weeks in saline of 3 mg benzo[a]pyrene or 3 mg ferric oxide or 3 mg ferric oxide plus 3 mg benzo[a]pyrene or 1.1 mg Sil-Co-Sil or 1.1 mg Sil-Co-Sil plus 3 mg benzo[a]pyrene or 0.7 mg Min-U-Sil or 0.7 mg Min-U-Sil plus 3 mg benzo[a]pyrene or 7 mg Min-U-Sil or 7 mg Min-U-Sil plus 3 mg benzo[a]pyrene. Fifty male controls received saline alone. Survivors were killed at 92 weeks after exposure. Co-exposures with silica caused an enhancement of the number of respir-atory tract tumours induced by benzo[a]pyrene

(mainly in the bronchus and lung) (Niemeier et al., 1986; Table 3.7).

3.9 Synthesis

Studies of the carcinogenicity of crystal-line silica in experimental animal models have shown quartz dust to be a lung carcinogen in rats following inhalation and intratracheal instilla-tion, but not in mice or hamsters. Rats are known to be more sensitive than are mice or hamsters to the induction of lung tumours due to other inhaled poorly soluble particles, such as carbon black (Mauderly et al., 1994).

Quartz-induced lymphoma incidence was also increased in several experiments in rats after intrapleural administration, and in one study in mice after subcutaneous administration. Tridymite- and cristobalite-induced lymphomas were observed in only a single experiment.

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Table 3.6 Incidence, numbers and histological types of lung tumours in female Wistar rats after inhalation exposure to quartz and/or Thorotrast

Treatment Number of ratsa

Lung tumours

Incidence Total number

Histological type

Observed Bronchiolo-alveolar adenoma

Bronchiolo-alveolar carcinoma

Squamous cell carcinoma

Controls 85 – – – – –Low-dose quartz 82 37 62 8 17 37High-dose quartz

82 43 69 13 26 30

Thorotrast (Tho) 87 3 6 – 5 1Low-dose quartz + Tho

87 39 68 10 28 30

High-dose quartz + Tho

87 57 98 16 47 35

a Without the animals sacrificed 0 and 6 months after the end of inhalation exposure.From Spiethoff et al. (1992)


4. Other Relevant Data4.1 Deposition and biopersistence

The inhalation of crystalline silica is associ-ated with various lung diseases including acute silicosis or lipoproteinosis, chronic nodular sili-cosis, and lung cancer. Exposure to silica dust may also cause renal and autoimmune diseases (Steenland & Goldsmith, 1995; Stratta et al., 2001; Cooper et al., 2002; Otsuki et al., 2007). In silicotic patients, alveolar macrophages collected by pulmonary lavage contain crystalline silica and at autopsy, elevated levels of quartz are found in the lungs and lymph nodes. Crystalline silica is poorly soluble and biopersistent; even after cessation of exposure, silicosis can progress and is a risk factor for the development of lung cancer (IARC, 1997).

Alveolar macrophages play a key role in silica-related toxicity, and therefore the cyto-toxic potency of silica particles determine the degree of silica-related pathogenicity (IARC,

1997; Donaldson & Borm, 1998). The stronger the cytotoxicity of crystalline silica to alveolar macrophages, the higher the intensity of the inflammatory reaction, and the longer the resi-dence time of the particle in the lung (Donaldson & Borm, 1998; Fenoglio et al., 2000a).

Rodent inhalation studies have investigated the relationship between intrinsic particle toxicity, persistent inflammation, altered macrophage-mediated clearance, and biopersis-tence in the lung (Warheit et al., 2007). Crystalline silica particles induce lung inflammation that persists even after cessation of exposure, with alveolar macrophages having reduced chemo-tactic responses and phagocytosis. Crystalline silica impairs macrophage-mediated clearance secondary to its cytotoxicity that allows these particles to accumulate and persist in the lungs (IARC, 1997). In humans, it is possible that co-exposure to tobacco smoke and crystalline silica may impair the clearance of these toxic particles (IARC, 2004).

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Table 3.7 Incidences of respiratory tract tumours in Syrian golden hamsters after intratracheal administration of quartz with or without benzo[a]pyrene

Treatment No. of animals

No. of animals with respiratory tract tumours

No. of respiratory tract tumoursa by site

Mean latency (wk)

Larynx Trachea Bronchus and lung

Saline control 48 0 0 0 0 –BaP 47 22 5 3 32 72.6Ferric oxide 50 1 1 0 0 62Ferric oxide + BaP 48 35b,c 5 6 69 70.2Sil-Co-Sil 50 0 0 0 0 –Sil-Co-Sil + BaP 50 36b,c 13 13 72 66.5Min-U-Sil 50 1 0 0 1 68Min-U-Sil + BaP 50 44b,c 10 2 111 68.5Min-U-Sil + ferric oxide 49 0 0 0 0 –Min-U-Sil + ferric oxide + BaP

50 38b,c 10 4 81 66.7

a Types of tumours: polyps, adenomas, carcinomas, squamous cell carcinomas, adenosquamous carcinomas, adenocarcinomas, sarcomas.b Statistically significantly higher (P < 0.00001; two-tailed Fisher Exact test) compared with the corresponding group not treated with BaP.c Statistically significantly higher (P < 0.01; two-tailed Fisher Exact test) compared with the BaP group.BaP, benzo[a]pyreneFrom Niemeier et al. (1986)


4.2 Mechanisms of carcinogenicity

It is generally accepted that alveolar macrophages and neutrophils play a central role in diseases associated with exposure to crystalline silica (Hamilton et al., 2008). An inflammation-based mechanism as described in IARC (1997) is a likely mechanism responsible for the induction of lung cancer associated with exposure to crys-talline silica, although reactive oxygen species can be directly generated by crystalline silica polymorphs themselves, and can be taken up by epithelial cells. For this reason, a direct effect on lung epithelial cells cannot be excluded (Schins, 2002; Fubini & Hubbard, 2003; Knaapen et al. 2004).

4.2.1 Physicochemical features of crystalline silica dusts associated with carcinogenicity

The major forms or polymorphs of crys-talline silica are the natural minerals quartz, tridymite, cristobalite, coesite, stishovite, and the artifical silica-based zeolites (porosils) (Fenoglio et al., 2000a). Humans have been exposed only to quartz, tridymite, cristobalite, the other forms being very rare. Several amorphous forms of silica exist, some of which were classified in Group 3 (not classifiable as to their carcinogenicity) in the previous IARC Monograph (IARC, 1997). Also, it has been shown that this cytotoxicity is lowered with lowering hydrophilicity (Fubini et al., 1999), which depends upon the circumstances under which the surface was created. For example, silica in fly ashes or volcanic dusts is generated at high temperatures, and is mostly hydrophobic.

The classification in Group 1 (carcinogenic to humans) of some silica polymorphs in the previous IARC Monograph (IARC, 1997) was preceded by a preamble indicating that crystalline silica did not show the same carcinogenic potency in all circumstances. Physicochemical features – poly-morph characteristics, associated contaminants

– may account for the differences found in humans and in experimental studies. Several studies on a large variety of silica samples, aiming to clarify the so-called “variability of quartz hazard” have indicated features and contami-nants that modulate the biological responses to silica as well as several surface characteristics that contribute to the carcinogenicity of a crys-talline silica particle (Donaldson & Borm, 1998; Fubini, 1998a; Elias et al., 2000; Donaldson et al., 2001). The larger potency of freshly ground dusts (e.g. as in sandblasting) has been confirmed in several studies; Vallyathan et al., 1995), as imme-diately after cleavage, a large number of surface-active radicals are formed that rapidly decay (Damm & Peukert, 2009). The association with clay or other aluminium-containing compounds inhibits most adverse effects (Duffin et al., 2001; Schins et al., 2002a), iron in traces may enhance the effects but an iron coverage inhibits cyto-toxicity and cell transformation (Fubini et al., 2001). One study on a large variety of commer-cial quartz dusts has shown a spectrum of vari-ability in oxidative stress and inflammogenicity in vitro and in vivo, which exceeds the differences previously found among different polymorphs (Bruch et al., 2004; Cakmak et al., 2004; Fubini et al., 2004; Seiler et al., 2004). Subtle differences in the level of contaminants appear to determine such variability. New studies in vitro and in vivo on synthesized nanoparticles of quartz (Warheit et al., 2007) indicate a variability of effects also at the nanoscale. These new data clearly show that more or less pathogenic materials are comprised under the term “crystalline silica dusts.” However, most studies, so far, have failed to identify strict criteria to distinguish between potentially more or less hazardous forms of crystalline silica.

The pathogenic potential of quartz seems to be related to its surface properties, and the surface properties may vary depending on the origin of the quartz. The large variability in silica hazard even within quartz particles of the same polymorph may originate from the

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grinding procedure, the particle shape, the thermal treatment (determines the hydrophi-licity of the particle), and the metal impurities (e.g. aluminium, iron) (Fubini et al., 2004).

The toxicity of silica dust from various sources may be related either to the kind of silica polymorph or to impurities.

The correlation between artificially pure crystalline silicas (porosils) with similar phys-icochemical properties, but different micromor-phology, size and surface area, was investigated (Fenoglio et al., 2000a). Surface area and aspect ratio (elongated crystals with a higher aspect ratio than more isometric crystals) of the particulates tested in a cellular system (mouse monocyte-macrophage tumour cell line) corre-late best with inhibition of cell proliferation after 24–72 hours experimental time. From the natural crystalline silicas, only stishovite did not show a cytotoxic effect; all the other natural polymorphs were rather toxic. Stishovite is made up of smooth round particles (Cerrato et al., 1995) whereas quartz, tridymite, and cristo-balite consist of particles with very sharp edges caused by grinding (Fubini, 1998a; Fubini et al., 1990, 1999). Stishovite, the only polymorph with silicon in octahedral coordination, has densely packed hydroxyl-silanols on its surface that interact with hydrogen bonds with each other; for this reason, the interaction of silanols with cell membranes, which normally does occur, is dramatically reduced (Cerrato et al., 1995).

Pure silica-zeolites with different particle forms exhibit similar cytotoxicity in vitro if compared at equal surface area instead of equal mass. The extent of free radical generation did not show a significant correlation with cytotox-icity in this short-term in-vitro test (Fenoglio et al., 2000a). Free radicals generated by the particle may play a role in later stages of toxicity related to crystalline silica (Ziemann et al., 2009). Both silicon-based surface radicals and iron ions located at the particle surface may be active

centres for free radical release in solution (Fubini et al., 2001).

As has already been demonstrated with quartz and cristobalite (Brown & Donaldson, 1996; Bégin et al., 1987), the cytotoxicity of artificially pure silica-zeolites can be decreased by aluminium ions adsorbed onto the particle surface (Fenoglio et al., 2000a). Crystalline silica may occur naturally embedded in clays or may be mixed with other materials in some commer-cial products. It is possible that these materials may adsorb onto the silica surface, and modify its reactivity. However, the extent of surface coverage and the potency of these modified crys-talline silica particles after long-term residence in the lungs have not been systematically assessed.

A quartz sample isolated from bentonite clay obtained from a 100 to 112 million-year-old formation in Wyoming, USA, exhibits a low degree of internal crystal organization, and the surface of this quartz particles are occluded by coatings of the clay. This “quartz isolate” was compared in respect to its toxic potency after intratracheal instillation in rats with the quartz sample DQ12. The “quartz isolate” showed a much lower toxicity than DQ12 quartz, in agree-ment with the much lower surface reactivity of “quartz isolate” compared to the DQ12 quartz (Creutzenberg et al., 2008; Miles et al., 2008).

4.2.2 Direct genotoxicity and cell transformation

Reactive oxygen species are generated not only at the particle surface of crystalline silica, but also by phagocytic and epithelial cells exposed to quartz particles (Castranova et al., 1991; Deshpande et al., 2002). Oxidants generated by silica particles and by the respiratory burst of silica-activated phagocytic cells may cause cellular and lung injury, including DNA damage. Lung injury may be initiated and amplified by severe inflammation (Donaldson et al., 2001; Castranova, 2004; Knaapen et al., 2004). Various

391


products (chemotactic factors, cytokines, growth factors) released by activated (and also dying) alveolar macrophages will not only recruit more macrophages as well as polymorphonuclear leukocytes (PMNs) and lymphocytes, but may also affect and activate bronchiolar and alveolar epithelial cells.

Reactive oxygen species can directly induce DNA damage (Knaapen et al., 2002; Schins et al., 2002b), and morphological transforma-tions observed in Syrian hamster embryo (SHE) cells correlate well with the amount of hydroxyl radicals generated (Elias et al., 2000, 2006; Fubini et al., 2001). Neoplastic transformation was observed in in-vitro assays in the absence of secondary inflammatory cells (Hersterberg et al., 1986; Saffiotti & Ahmed, 1995; Elias et al., 2000). There seems to be no correlation between the extent of cytotoxicity as assessed by colony-forming efficiency and transforming potency (SHE test) when various quartz samples were investigated (Elias et al., 2000). In contrast to transforming potency, which was clearly related to hydroxyl radical generation, cytotoxicity was not affected by antioxidants. Partial reduction of transforming potency when deferoxamine-treated quartz was used points to the role of tran-sitional metals, e.g. iron on the particle surface in generating hydroxyl radicals (Fubini et al., 2001). The SHE test used in this study by Fubini et al. (2001) and by others is recommended by the Centre for the Validation of Alternative Methods (ECVAM) as an alternative method for investi-gating the potential carcinogenicity of particu-lates (Fubini, 1998b). In nude mice injected with these transformed cells, tumours could be initi-ated (Saffiotti & Ahmed, 1995).

Particle uptake by target cells is also relevant for direct genotoxicity (Schins, 2002). Crystalline silica particles were detected in type II lung epithelial cells (RLE-6TN) in vitro; these parti-cles were located also in close proximity to the nuclei and mitochondria, but not within these organelles. An osteosarcoma cell line lacking

functional mitochondria was investigated with respect to quartz-related DNA damage with an osteosarcoma cell line with normal mitochon-dria. Only the cell line with functioning mito-chondria showed significantly increased DNA damage after exposure to DQ12 quartz (Li et al., 2007).

The relationship between genotoxic effects (formation of DNA strand breaks) and the uptake of quartz particles was investigated in vitro with A549 human lung epithelial cells (Schins et al., 2002a). The percentage of A549 cells containing particles was clearly lower after exposure to quartz coated with polyvinylpynidine-N-oxide or aluminum lactate compared to uncoated quartz (DQ12). In this experiment, DNA strand breaks measured (Comet assay) in the exposed cells correlated very well with the number of particles absorbed by the cells. It could also be demonstrated that the generation of reac-tive oxygen species was closely related to the formation of DNA strand breaks (Schins, 2002). However, in other in-vitro studies using different quartz species, DNA strand breaks in epithelial cells could be observed only at particle concen-trations that caused cytotoxicity (Cakmak et al., 2004).

Rats were exposed to crystalline silica for 3 hours and sacrificed at different time points after exposure, and lungs were examined by electron microscopy. The lungs were fixed by vascular perfusion through the right ventricle. In these investigations, silica crystals were found within the cytoplasm of type I lung epithelial cells (Brody et al., 1982). Although type I cells are not the target cell for tumour formation, these data show that the uptake of quartz parti-cles in epithelial lung cells in vivo is in principle possible. Other particles including titanium dioxide, carbon black, or metallic particles have occasionally been found in type I lung epithelial cells in rats after inhalation exposure (Anttila, 1986; Anttila et al., 1988; Nolte et al., 1994).

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After intratracheal instillation of DQ12 quartz, DNA strand breaks could be observed in lung epithelial cells isolated from quartz-treated rats. This effect was not found when the quartz dust was treated with either polyvi-nylpyridine-N-oxide or aluminium lactate. This finding suggests an important role of the reac-tive surface of quartz-induced DNA damage in vivo. No increase in alkaline phosphatase was found in the bronchiolo-alveolar lavage fluid of quartz-treated rats, and therefore, as alkaline phosphatase is an enzyme specifically present in type II epithelial cells, it can be assumed that there was no obvious cytotoxicity in these lung cells. These data support the current view of the important role of inflammatory cells in quartz-induced genotoxic effects (Knaapen et al., 2002).

4.2.3 Depletion of antioxidant defences

Substantial amounts of ascorbic acid (Fenoglio et al., 2000b) and glutathione (Fenoglio et al., 2003) are consumed in the presence of quartz in cell-free tests via two different surface reactions. Both reactions may deplete antioxidant defences in the lung-lining fluid, thereby enhancing the extent of oxidative damage.

Incubation of murine alveolar MH-S macrophages with quartz particles (80 μg/cm2) for 24 hours inhibited glucose 6-phosphate dehy-drogenase (G6PD)-1 activity by 70%, and the pentose phosphate pathway by 30%. Such effects were accompanied by a 50% decrease in intra-cellular glutathione. Quartz inhibits G6PD but not other oxidoreductases, and this inhibition is prevented by glutathione, suggesting that silica contributes to oxidative stress also by inhibiting the pentose phosphate pathway, which is crit-ical for the regeneration of reduced glutathione (Polimeni et al., 2008).

4.2.4 Indirect mechanisms

After 13 weeks of inhalation exposure to 3 mg/m3 crystalline silica (mass median aerody-namic diameter, 1.3 μm) or 50 mg/m3 amorphous silica (mass median aerodynamic diameter, 0.81 μm), the percentage of PMNs in the lung of the exposed rats was similar after each exposure. However, HPRT mutation frequency of the alve-olar epithelial cells was significantly increased only in rats exposed to crystalline silica. Other factors including toxic effects to epithelial cells, solubility, and biopersistence may also be impor-tant for the induction of these mutagenic effects (Johnston et al., 2000). A specific finding in rats treated intratracheally with amorphous silica (Aerosil®150, pyrogenic silica with primary particle size of 14 nm) was a severe granuloma-tous alveolitis which over time progressed to “scar-like” interstitial fibrotic granulomas not seen after crystalline silica exposure in rats (Ernst et al., 2002). Lung tumours were found in rats also after the repeated intratracheal instilla-tion of the same amorphous silica (Kolling et al., 2008).

Toxic mineral dusts, especially crystalline silica, have unique, potent effects on alveolar macrophages that have been postulated to trigger the chain of events leading to chronic lung fibrosis (silicosis) and lung cancer (Hamilton et al., 2008). Macrophages express a variety of cell-surface receptors that bind to mineral dusts leading to phagocytosis, macrophage apoptosis, or macrophage activation. The major macrophage receptor that recognizes and binds inhaled parti-cles as well as unopsonized bacteria is MARCO (Arredouani et al., 2004, 2005). Additional members of the macrophage-scavenger receptor family responsible for binding mineral parti-cles as well as a wide range of other ligands include SR-AI and SR-AII (Murphy et al., 2005). Although SR-AI/II and MARCO bind both toxic and non-toxic particles, only crystalline silica triggers macrophage apoptosis following

393


binding to these scavenger receptors (Hamilton et al., 2008). Other receptors expressed by macrophages and other target cells in the lung that bind mineral dusts include complement receptor and mannose receptors (Gordon, 2002). The pathological consequences of silica-induced injury to alveolar macrophages followed by apoptosis is impaired alveolar-macrophage-mediated clearance of crystalline silica as discussed in Section 4.1. Lysosomal membrane permeabilization following phagocytosis of crys-talline silica particles has been hypothesized to enhance IL-1β secretion (Hornung et al., 2008), and to trigger the release of cathepsin D, leading to mitochondrial damage, and the apoptosis of alveolar macrophages (Thibodeau et al., 2004). Macrophage injury and apoptosis may be respon-sible for the increased susceptibility of workers exposed to silica to develop autoimmune disease (Pfau et al., 2004; Brown et al., 2005), and pulmo-nary tuberculosis (IARC, 1997; Huaux, 2007).

Persistent inflammation triggered by crystal-line silica (quartz) has been linked to indirect genotoxicity in lung epithelial cells in rats, see Fig. 4.1 (IARC, 1997). Rats exposed to crystalline silica develop a severe, prolonged inflammatory response characterized by elevated neutrophils, epithelial cell proliferation, and development of lung tumours (Driscoll et al., 1997). These persis-tent inflammatory and epithelial proliferative responses are less intense in mice and hamsters, and these species do not develop lung tumours following exposure to crystalline silica or other poorly soluble particles (IARC, 1997). There has been considerable discussion of whether the response of rats to inhaled particles is an appro-priate model for the exposed response of humans (ILSI, 2000). Comparative histopathological studies of rats and humans exposed to the same particulate stimuli reveal more severe inflam-mation, alveolar lipoproteinosis, and alveolar epithelial hyperplasia in rats than in humans (Green et al., 2007). These studies suggest that rats are more susceptible to develop persistent

lung inflammation in response to particle inha-lation than other species (ILSI, 2000).

Chronic exposure of rats to crystal-line silica also leads to pulmonary fibrosis (Oberdörster, 1996), and workers with silicosis have an elevated risk of developing lung cancer (Pelucchi et al., 2006). The causal association between chronic inflammation, fibrosis, and lung cancer was reviewed by IARC (2002). These associations provide a biological plausible mech-anism between inflammation and the develop-ment of fibrosis and/or lung cancer (Balkwill & Mantovani, 2001).

4.3 Molecular pathogenesis of cancer of the lung

Acquired molecular alterations in oncogenes and tumour-suppressor genes characterize the multistage development of lung cancer (Sato et al., 2007). Somatic alterations, such as DNA adducts, develop in the respiratory tract of smokers during the early stages of carcinogenesis (Wiencke et al., 1999). Specific point mutations in in the K-RAS oncogene and the p53 tumour-suppressor gene are considered as biomarkers of exposure to chemical carcinogens in tobacco smoke (Pfeifer et al., 2002). Only one study has investigated the mutational spectrum of these genes that may be used as biomarkers for exposure to crystal-line silica. Liu et al. (2000) analysed the muta-tion spectra in the K-RAS and p53 genes in lung cancers that developed in workers with silicosis [smoking status unknown]. In a series of 36 cases, 16 mutations in exons 5, 7 and 8 of the p53 gene were found. In contrast to non-occupational lung cancers, seven of these mutations clustered in exon 8. Most of the K-RAS gene mutations in non-small cell lung carcinomas occur at codon 12. Liu et al. (2000) did not detect this muta-tion in their case series of silicotics. Six muta-tions were found at codon 15 in exon 1 as well as additional mutations in codons 7, 15, 20, and

394


21. Most of these mutations were G→C transver-sions in contrast to G→T transversions at codon 12, which are characteristic of non-small cell lung cancers associated with tobacco smoking. If these specific mutations are confirmed in a larger series of lung cancers in silicotics, these could provide early biomarkers for the develop-ment of lung cancer in workers exposed to crys-talline silica.

In a rat model of silica-induced lung cancer, a low frequency of p53 gene mutations and no

mutations in K-RAS, N-RAS, or c-H-RAS onco-genes were observed (Blanco et al., 2007). No mutations in oncogenes or tumour-suppressor genes have been directly linked with exposure to crystalline silica.

The epigenetic silencing of the p16INK4a (Belinsky et al., 2002), CDH13, and APC genes has also been found in a rat model of lung cancer induced by intratracheal instillation of crystalline silica (Blanco et al., 2007). In this rodent model, the increased expression of iNOS

395

Fig. 4.1 Proposed mechanisms for the carcinogenicity of crystalline silica in rats

Crystalline Silica

Macrophages

IMPAIRED CLEARANCE Oxidants

Cytokines, chemokines

Persistent inflammation: neutrophils particle retention

Cytokines

Oxidants

Epithelial cell injury, proliferation

Genetic alterations

Lung cancer


(inducible nitric oxide synthase) was also found in preneoplastic lesions, which is consistent with a role for reactive nitrogen species in silicosis (Porter et al., 2006).

4.4 Species differences and susceptible populations

In rat chronic inhalation studies using crys-talline silica or granular, poorly soluble particles, female rats are more susceptible than males to the induction of lung tumours. Overall, rats are susceptible to the induction of lung cancer following the exposure to crystalline silica or granular, poorly soluble particles, but hamsters and mice are more resistant. The mechanistic basis for these sex and species differences is unknown. Mice exposed to crystalline silica by intranasal instillation or subcutaneous injection, as well as rats injected intrapleurally or intraperi-toneally develop lymphomas. Following inhala-tion exposure to crystalline silica, lymphomas have not been observed in any species (see Section 3).

In some workers exposed to crystalline silica, cytokine gene polymorphisms have been linked with silicosis (Yucesoy et al., 2002). Specific polymorphisms in genes encoding in TNF-α and IL-1RA (interleukin-1 receptor antagonist) have been associated with an increased risk for the development of silicosis (Yucesoy & Luster, 2007). Gene–linkage analyses might reveal addi-tional markers for susceptibility to the devel-opment of silicosis and lung cancer in workers exposed to crystalline silica.

4.5 Synthesis

Three mechanisms have been proposed for the carcinogenicity of crystalline silica in rats (Fig. 4.1). First, exposure to crystalline silica impairs alveolar-macrophage-mediated particle clearance thereby increasing persistence of silica

in the lungs, which results in macrophage acti-vation, and the sustained release of chemokines and cytokines. In rats, persistent inflammation is characterized by neutrophils that generate oxidants that induce genotoxicity, injury, and proliferation of lung epithelial cells leading to the development of lung cancer. Second, extra-cellular generation of free radicals by crystalline silica depletes antioxidants in the lung-lining fluid, and induces epithelial cell injury followed by epithelial cell proliferation. Third, crystalline silica particles are taken up by epithelial cells followed by intracellular generation of free radi-cals that directly induce genotoxicity.

The Working Group considers the first mechanism as the most prominent based on the current experimental data using inhalation or intratracheal instillation in rats, although the other mechanisms cannot be excluded. It is unknown which of these mechanisms occur in humans exposed to crystalline silica dust. The mechanism responsible for the induction of lymphomas in rats and mice following direct injections of crystalline silica dust is unknown.

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of crystalline silica in the form of quartz or cristobalite. Crystalline silica in the form of quartz or cristobalite dust causes cancer of the lung.

There is sufficient evidence in experimental animals for the carcinogenicity of quartz dust.

There is limited evidence in experimental animals for the carcinogenicity of tridymite dust and cristobalite dust.

Crystalline silica in the form of quartz or cris-tobalite dust is carcinogenic to humans (Group 1).

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silica dust, crystalline, in the form of quartz or cristobalite